Pyrrolyl intermediates in the synthesis of pyrrole analogs of mevalonolactone and derivatives thereof

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR2##  wherein R 5 , R 6  and R 7  are as defined below, R 2  is C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR3##  wherein R 8 , R 9  and R 10  are as defined below, R 3  is hydrogen, C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR4##  wherein R 11 , R 12  and R 13  are as defined below, R 4  is hydrogen, C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR5## wherein R 14 , R 15  and R 16  are as defined below, X is --(CH 2 ) m  --, --CH═CH--, --CH═CH--CH 2  --or --CH 2  --CH═CH--, wherein m is 0, 1, 2 or 3, and 
     Z is ##STR6##  wherein R 17  is hydrogen or C 1-3  alkyl, and 
     R 18  is hydrogen, R 19  or M, 
      wherein 
     R 19  is a physiologically acceptable ester group, and 
     M is a pharmaceutically acceptable cation, 
     wherein 
     each of R 5 , R 8 , R 11  and R 14  is independently hydrogen, C 1-3  alkyl, n-butyl, i-butyl, t-butyl, C 1-3  alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, 
     each of R 6 , R 9 , R 12  and R 15  is independently hydrogen, C 1-3  alkyl, C 1-3  alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and 
     each of R 7 , R 10 , R 13  and R 16  is independently hydrogen, C 1-2  alkyl, C 1-2  alkoxy, fluoro or chloro, 
     with the provisos that not more than one substituent on each of Rings A, B, C and D independently is trifluoromethyl, not more than one substituent on each of Rings A, B, C and D independently is phenoxy, and not more than one substituent on each of Rings A, B, C and D independently is benzyloxy, 
     with the provisos that (i) the -X-Z group is in the 2- or 3-position of the pyrrole ring, (ii) the -X-Z group is ortho to both R 1  and R 2  and (iii) R 3  is ortho to R 2 , the use thereof for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis, pharmaceutical compositions comprising such compounds and processes for and intermediates in the synthesis of such compounds.

This is a division of application Ser. No. 919,275, filed Oct. 15, 1986, now U.S. Pat. No. 4,851,427, which is a continuation-in-part of application Ser. No. 06/791,198, filed Oct. 25, 1985 and now abandoned.

This invention relates to compounds of the formula ##STR7## wherein R₁ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR8## wherein R₅, R₆ and R₇ are as defined below, R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR9## wherein R₈, R₉ and R₁₀ are as defined below, R₃ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR10## wherein R₁₁, R₁₂ and R₁₃ are as defined below, R₄ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR11## wherein R₁₄, R₁₅ and R₁₆ are as defined below, X is --(CH₂)_(m) --, --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, wherein m is 0, 1, 2 or 3, and ##STR12## wherein R₁₇ is hydrogen or C₁₋₃ alkyl, and

R₁₈ is hydrogen, R₁₉ or M,

wherein

R₁₉ is a physiologically acceptable ester group, and

M is a pharmaceutically acceptable cation,

wherein

each of R₅, R₈, R₁₁ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy,

each of R₆, R₉, R₁₂ and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R₇, R₁₀, R₁₃ and R₁₆ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro,

with the provisos that not more than one substituent on each of Rings A, B, C and D independently is trifluoromethyl, not more than one substituent on each of Rings A, B, C and D independently is phenoxy, and not more than one substituent on each of Rings A, B, C and D independently is benzyloxy,

with the provisos that (i) the --X--Z group is in the 2- or 3-position of the pyrrole ring, (ii) the --X--Z group is ortho to both R₁ and R₂, and (iii) R₃ is ortho to R₂, processes for and intermediates in the synthesis thereof, pharmaceutical compositions comprising a compound of Formula I and the use of the compounds of Formula I for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.

By the term "physiologically acceptable ester group" is meant a group which, together with the --COO--radical to which it is attached, forms an ester group which is physiologically acceptable. The preferred such groups are the physiologically acceptable and hydrolyzable ester groups. By the term "physiologically acceptable and hydrolyzable ester group" is meant a group which, together with the --COO--radical to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions to yield a compound of Formula I wherein R₁₈ is hydrogen and an alcohol which itself is physiologically acceptable, i.e., non-toxic at the desired dosage level, and which, preferably, is free of centers of asymmetry. Examples of such groups are C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl and benzyl, collectively referred to as R'₁₉.

For the avoidance of doubt, throughout this specification it is the right-hand side of the X radical that is attached to the Z group.

As is self-evident to those in the art, each compound of Formula I (and every subscope and species thereof) has two centers of asymmetry (the two carbon atoms bearing the hydroxy groups in the group of Formula a and the carbon atom bearing the hydroxy group and the carbon atom having the free valence in the group of Formula b) and, therefore, there are four stereoisomeric forms (enantiomers) of each compound (two racemates or pairs of diastereoisomers), provided that R₁₈ does not contain any center of asymmetry. The four stereoisomers may be designated as the R,R, R,S, S,R and S,S enantiomers, all four stereoisomers being within the scope of this invention. When R₁₈ contains one or more centers of asymmetry, there are eight or more stereoisomers. Since it is preferred that R₁₈ not contain a center of asymmetry and for reasons of simplicity any additional stereoisomers resulting from the presence of one or more centers of asymmetry in R₁₈ usually will be ignored, it being assumed that R₁₈ is free of centers of asymmetry.

The compounds of Formula I may be divided into two groups, viz., those of Formulae IB and IC: ##STR13##

The compounds of each of Groups IB and IC may be divided into two subgroups based upon the significance of Z, viz., Group IBa (the compounds of Group IB wherein Z is a group of Formula a), Group IBb (the compounds of Group IB wherein Z is a group of Formula b), Group ICa (the compounds of Group IC wherein Z is a group of Formula a) and Group ICb (the compounds of Group IC wherein Z is a group of Formula b).

Preferably, one of R₁ and R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom and the other is Ring A (if R₁) or Ring B (if R₂). Also preferably, one of R₃ and R₄ is Ring C (if R₃) or Ring D (if R₄) and the other is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, preferably hydrogen or C₁₋₂ alkyl and most preferably hydrogen, except that R₄ in Formula IC is preferably other than hydrogen. More preferably, the preferences of both preceding sentences occur simultaneously. Thus, the preferred compounds of Formula I and each of the subscopes thereof are those having attached to the pyrrole ring (i) Ring A or Ring B, (ii) Ring C or Ring D, and (iii) two alkyl groups or, in the case of the compounds of Formula IB, especially one alkyl group and one hydrogen atom. Even more preferably, Ring A or Ring B, as the case may be, and Ring C or Ring D, as the case may be, are ortho to each other.

Also preferably, the pyrrole ring does not bear two ortho tertiary alkyl groups.

In Formula IB:

R₁ is preferably R_(1Bx), where R_(1Bx) is Ring A, more preferably R'_(1Bx), where R'_(1Bx) is Ring A wherein R₅ is R'₅, R₆ is R'₆, and R₇ is R'₇, even more preferably R"_(1Bx), where R"_(1Bx) is Ring A wherein R₅ is R"₅, R₆ is R"₆, and R₇ is hydrogen, and most preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl; or

R₁ is preferably R_(1By), where R_(1By) is C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(1By), where R'_(1By) is C₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferably i-propyl.

R₂ is preferably R_(2Bx), where R_(2Bx) is C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(2Bx), where R'_(2Bx) is C₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferably i-propyl; or

R₂ is preferably R_(2By), where R_(2By) is Ring B, more preferably R'_(2By), where R'_(2By) is Ring B wherein R₈ is R'₈, R₉ is R'₉, and R₁₀ is R'₁₀, even more preferably R"_(2By), where R"_(2By) is Ring B wherein R₈ is R"₈, R₉ is R"₉, and R₁₀ is hydrogen, and most preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl.

R₃ is preferably R_(3Bx), where R_(3Bx) is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(3Bx), where R'_(3Bx) is hydrogen or C₁₋₂ alkyl, even more preferably R"_(3Bx), where R"_(3Bx) is hydrogen or methyl, and most preferably hydrogen; or

R₃ is preferably R_(3By), where R_(3By) is Ring C, more preferably R'_(3By), where R'_(3By) is Ring C wherein R₁₁ is R'₁₁, R₁₂ is R'₁₂, and R₁₃ is R'₁₃, even more preferably R"_(3By), where R"_(3By) is Ring C wherein R₁₁ is R"₁₁, R₁₂ is R"₁₂, and R₁₃ is hydrogen, and most preferably phenyl.

R₄ is preferably R_(4Bx), where R_(4Bx) is Ring D, more preferably R'_(4Bx), where R'_(4Bx) is Ring D wherein R₁₄ is R'₁₄, R₁₅ is R'₁₅, and R₁₆ is R'₁₆, even more preferably R"_(4Bx), where R"_(4Bx) is Ring D wherein R₁₄ is R"₁₄, R₁₅ is R"₁₅, and R₁₆ is hydrogen, and most preferably phenyl; or

R₄ is preferably R_(4By), where R_(4By) is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(4By), where R'_(4By) is hydrogen or C₁₋₂ alkyl, even more preferably R"_(4By), where R"4By is hydrogen or methyl, and most preferably hydrogen.

In Formula IC:

R₁ is preferably R_(1Cx), where R_(1Cx) is C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(1Cx), where R'_(1Cx) is C₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferably i-propyl; or

R₁ is preferably R_(1Cy), where R_(1Cy) is Ring A, more preferably R'_(1Cy), where R'_(1Cy) is Ring A wherein R₅ is R'₅, R₆ is R'₆, and R₇ is R'₇, even more preferably R"_(1Cy), where R"_(1Cy) is Ring A wherein R₅ is R"₅, R₆ is R"₆, and R₇ is hydrogen, and most preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl.

R₂ is preferably R_(2Cx), where R_(2Cx) is Ring B, more preferably R'_(2Cx), where R'_(2Cx) is Ring B wherein R₈ is R'₈, R₉ is R'₉, and R₁₀ is R'₁₀, even more preferably R"_(2Cx), where R"_(2Cx) is Ring B wherein R₈ is R"₈, R₉ is R"₉, and R₁₀ is hydrogen, and most preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl; or

R₂ is preferably R_(2Cy), where R_(2Cy) is C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(2Cy), where R'_(2Cy) is C₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferably i-propyl.

R₃ is preferably R_(3Cx), where R_(3Cx) is Ring C, more preferably R'_(3Cx), where R'_(3Cx) is Ring C wherein R₁₁ is R'₁₁, R₁₂ is R'₁₂, and R₁₃ is R'₁₃, even more preferably R"_(3Cx), where R"_(3Cx) is Ring C wherein R₁₁ is R"₁₁, R₁₂ is R"₁₂, and R₁₃ is hydrogen, and most preferably phenyl; or

R₃ is preferably R_(3Cy), where R_(3Cy) is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(3Cy), where R_(3Cy) is hydrogen or C₁₋₂ alkyl, and even more preferably R"_(3Cy), where R"_(3Cy) is hydrogen or methyl, especially hydrogen.

R₄ is preferably R_(4Cx), where R_(4Cx) is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R'_(4Cx), where R'_(4Cx) is C₁₋₂ alkyl, and most preferably methyl; or

R₄ is preferably R_(4Cy), where R_(4Cy) is Ring D, more preferably R'_(4Cy), where R'_(4Cy) is Ring D wherein R₁₄ is R'₁₄, R₁₅ is R'₁₅, and R₁₆ is R'₁₆, even more preferably R"_(4Cy), where R"_(4Cy) is Ring D wherein R₁₄ is R"₁₄, R₁₅ is R"₁₅, and R₁₆ is hydrogen, and most preferably phenyl.

In both formulae:

Each of R₅, R₈, R₁₁ and R₁₄ is preferably R'₅, R'₈, R'₁₁ and R'₁₄, respectively, where each of R'₅, R'₈, R'₁₁ and R'₁₄ is independently hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl, fluoro or chloro, and more preferably R"₅, R"₈, R"₁₁ and R"₁₄, respectively, where each of R"₅, R"₈, R"₁₁ and R"₁₄ is independently hydrogen, methyl or fluoro. R"₅ and R"₈ are most preferably fluoro, especially 4-fluoro, and R"₁₁ and R"₁₄ are most preferably hydrogen.

Each of R₆, R₉, R₁₂ and R₁₅ is preferably R'₆, R'₉, R'₁₂ and R'₁₅, respectively, where each of R'₆, R'₉, R'₁₂ and R'₁₅ is independently hydrogen, C₁₋₂ alkyl, fluoro or chloro, more preferably R"₆, R"₉, R"₁₂ and R"₁₅, respectively, where each of R"₆, R"₉, R"₁₂ and R"₁₅ is independently hydrogen or methyl, and most preferably hydrogen.

Each of R₇, R₁₀, R₁₃ and R₁₆ is preferably R'₇, R'₁₀, R'₁₃ and R'₆, respectively, where each of R'₇, R'₁₀, R'₁₃ and R'₁₆ is independently hydrogen or methyl, and most preferably hydrogen.

Preferably, each of Rings A, B, C and D independently bears a maximum of one substituent selected from the group consisting of t-butyl, trifluoromethyl, phenyl, phenoxy and benzyloxy. More preferably, when any two or all three of the substituents on Ring A [R₅ (R'₅, etc.), R₆ (R'₆, etc.) and R₇ (R'₇, etc.)], Ring B [R₈ (R'₈, etc.), R₉ (R'₉, etc.) and R₁₀ (R'₁₀, etc.)], Ring C [R₁₁ (R'₁₁, etc.), R₁₂ (R'₁₂, etc.) and R₁₃ (R'₁₃, etc.)] and Ring D [R₁₄ (R'₁₄, etc.), R₁₅ (R'₁₅, etc.) and R₁₆ (R'₁₆, etc.)] independently are ortho to each other, at least one member of each pair that are ortho to each other is a member of the group consisting of hydrogen, methyl, methoxy, fluoro and chloro. Also more preferably, at least one of the ortho positions of each of Rings A, B, C and D independently has a member of the group consisting of hydrogen, fluoro and methyl.

Each of Rings A and B independently is preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyl, more preferably the latter two and most preferably 4-fluorophenyl.

Each of Rings C and D is preferably phenyl.

R₁₇ is preferably R'₁₇, where R'₁₇ is hydrogen or methyl, and most preferably hydrogen.

R₁₈ is preferably R'₁₈, where R'₁₈ is hydrogen, R'₁₉ or M, more preferably R"₁₈, where R"₁₈ is hydrogen, C₁₋₃ alkyl or M, even more preferably R"'₁₈, where R"'₁₈ is hydrogen, C₁₋₂ alkyl or M, and most preferably M, particularly M' and especially sodium.

R₁₉ is preferably a physiologically acceptable and hydrolyzable ester group, more preferably R'₁₉, where R'₁₉ is C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl, even more preferably R"₁₉, where R"₁₉ is C₁₋₃ alkyl, and most preferably R"'₁₉, where R"'₁₉ is C₁₋₂ alkyl, especially ethyl.

Any --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH-- as X is preferably trans, i.e., (E).

X is preferably X', where X' is --CH₂ CH₂ -- or --CH═CH--, and most preferably ##STR14## (i.e., (E)--CH═CH--).

Z is preferably a group of Formula a wherein R₁₇ is R'₁₇ (especially hydrogen), and R₁₈ is R'₁₈ or a group of Formula b wherein R₁₇ is R'₁₇ (especially hydrogen), more preferably a group of Formula a wherein R₁₇ is hydrogen, and R₁₈ is R"₁₈ or a group of Formula b wherein R₁₇ is hydrogen, even more preferably a group of Formula a wherein R₁₇ is hydrogen, and R₁₈ is R"'₁₈ or a group of Formula b wherein R₁₇ is hydrogen, and most preferably a group of Formula a wherein R₁₇ is hydrogen, and R₁₈ is M, preferably M' and especially sodium.

m is preferably m', where m' is 2 or 3, and most preferably 2.

M is preferably free from centers of asymmetry and is more preferably M', i.e., sodium, potassium or ammonium, and most preferably sodium. For simplicity, each formula in which M appears has been written as if M were monovalent and, preferably, it is. However, it may also be divalent or trivalent and, when it is, it balances the charge of two or three carboxy groups, respectively. Thus, Formula I and every other formula containing an M embraces compounds wherein M is divalent or trivalent, i.e., compounds containing two or three carboxylate-containing anions per cation M.

As between otherwise identical compounds of Formula I, those wherein Z is a group of Formula a are generally preferred over those wherein Z is a group of Formula b.

Insofar as the compounds of Groups IBa and ICa and each of the subgroups thereof are concerned, the erythro isomers are preferred over the threo isomers, erythro and threo referring to the relative positions of the hydroxy groups in the 3- and 5-positions of the group of Formula a.

Insofar as the compounds of Groups IBb and ICb and each of the subgroups thereof are concerned, the trans lactones are generally preferred over the cis lactones, cis and trans referring to the relative positions of R₁₇ and the hydrogen atom in the 6-position of the group of Formula b.

The preferred stereoisomers of the compounds of Formula I having only two centers of asymmetry wherein X is a direct bond, --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula a are the 3R,5S isomer and the racemate of which it is a constituent, i.e., the 3R,5S-3S,5R (erythro) racemate

The preferred stereoisomers of the compounds of Formula I having only two centers of asymmetry wherein X is --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- or --CH═CH--CH₂ --, and Z is a group of Formula a are the 3R,5R isomer and the racemate of which it is a constituent, i.e., the 3R,5R-3S,5S (erythro) racemate

The preferences set forth in the preceding two paragraphs also apply to the compounds of Formula I having more than two centers of asymmetry and represent the preferred configurations of the indicated positions.

The preferred stereoisomers of the compounds of Formula I wherein X is a direct bond, --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula b are the 4R,6S and 4R,6R isomers and the racemate of which each is a constituent, i.e., the 4R,6S-4S,6R (trans lactone) and 4R,6R-4S,6S (cis lactone) racemates, with the 4R,6S isomer and the racemate of which it is a constituent being more preferred.

The preferred stereoisomers of the compounds of Formula I wherein X is --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- or --CH═CH--CH₂ --, and Z is a group of Formula b are the 4R,6R and 4R,6S isomers and the racemate of which each is a constituent, i.e., the 4R,6R-4S,6S (trans lactone) and 4R,6S-4S,6R (cis lactone) racemates, with the 4R,6R isomer and the racemate of which it is a constituent being more preferred.

Each of the preferences set forth above applies, not only to the compounds of Formula I, but also to the compounds of Formulae IB and IC and those of Groups IBa, IBb, ICa and ICb as well as to every other subgroup thereof set forth in the specification, e.g., Groups (i) et seq., unless otherwise indicated. When any preference or group contains a variable, the preferred significances of that variable apply to the preference or group in question, unless otherwise indicated.

Preferred groups of compounds of Groups IBa, IBb, ICa and ICb include the compounds

(i) of Group IBa wherein R₁ is R_(1Bx), R₂ is R_(2Bx), R₃ is R_(3Bx), R₄ is R_(4Bx), R₁₇ is R'₁₇, R₁₈ is R'₁₈, and X is X',

(ii) of (i) wherein R₁ is R_(1Bx), R₂ is R'_(2Bx), R₃ is R'_(3Bx), R₄ is R'_(4Bx), R₁₇ is hydrogen, R₁₈ is R"₁₈, and X is (E)--CH═CH--,

(iii) of (ii) wherein R₁ is R"_(1Bx), R₃ is R"_(3Bx), R₄ is R"_(4Bx), and R₁₈ is R"'₁₈, preferably M,

(iv) of Group IBa wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3By), R₄ is R_(4By), R₁₇ is R'₁₇, R₁₈ is R'₁₈, and X is X',

(v) of (iv) wherein R₁ is R'_(1By), R₂ is R'_(2By), R₃ is R'_(3By), R₄ is R'_(4By), R₁₇ is hydrogen, R₁₈ is R"₁₈, and X is (E)--CH═CH--,

(vi) of (v) wherein R₂ is R"_(2By), R₃ is R"_(3By), R₄ is R"4By, and R₁₈ is R"'₁₈, preferably M,

(vii) of Group IBa wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3Bx), R₄ is R_(4Bx), R₁₇ is R'₁₇, R₁₈ and R'₁₈, and X is X',

(viii) of (vii) wherein R₁ is R'_(1By), R₂ is R'_(2By), R₃ is R'_(3Bx), R₄ is R'_(4Bx), R₁₇ is hydrogen, R₁₈ is R"₁₈, and X is (E)--CH═CH--,

(ix) of (viii) wherein R₂ is R"_(2By), R₃ is R"_(3Bx), R₄ is R"_(4Bx), and R₁₈ is R"'₁₈, preferably M,

(x)-(xviii) of (i)-(ix) wherein the hydroxy groups in the 3- and 5-positions of the group of Formula a have the erythro configuration,

(xix) of Group IBb wherein R₁ is R_(1Bx), R₂ is R_(2Bx), R₃ is R_(3Bx), R₄ is R_(4Bx), R₁₇ is R₁₇, and X is X',

(xx) of (xix) wherein R₁ is R'_(1Bx), R₂ is R'_(2Bx), R₃ is R'_(3Bx), R₄ is R'_(4Bx), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(xxi) of (xx) wherein R₁ is R"_(1Bx), R₃ is R"_(3Bx), and R₄ is R"_(4Bx),

(xxii) of Group IBb wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3By), R₄ is R_(4By), R₁₇ is R'₁₇, and X is X',

(xxiii) of (xxii) wherein R₁ is R'_(1By), R₂ is R'_(2By), R₃ is R'_(3By), R₄ is R'_(4By), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(xxiv) of (xxiii) wherein R₂ is R"_(2By), R₃ is R"_(3By), and R₄ is R"_(4By),

(xxv) of Group IBb wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3Bx), R₄ is R_(4Bx), R₁₇ is R'₁₇, and X is X',

(xxvi) of (xxv) wherein R₁ is R'_(1By), R₂ is R'_(2By), R₃ is R'_(3Bx), R₄ is R'_(4Bx), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(xxvii) of (xxvi) wherein R₂ is R"_(2By), R₃ is R"_(3Bx), and R₄ is R"_(4Bx),

(xxviii)-(xxxvi) of (xix)-(xxvii) wherein R₁₇ and the hydrogen atom in the 6-position of the group of Formula b are trans to each other, i.e., the trans lactones,

(xxxvii) of Group ICa wherein R₁ is R_(1Cx), R₂ is R_(2Cx), R₃ is R_(3Cx), R₄ is R_(4Cx), R₁₇ is R'₁₇, R₁₈ is R'₁₈, and X is X',

(xxxviii) of (xxxvii) wherein R₁ is R'_(1Cx), R₂ is R'_(2Cx), R₃ is R'_(3Cx), R₄ is R'_(4Cx), R₁₇ is hydrogen, R₁₈ is R"₁₈, and X is (E)--CH═CH--,

(xxxix) of (xxxviii) wherein R₂ is R"_(2Cx), R₃ is R"_(3Cx), R₄ is methyl, and R₁₈ is R"'₁₈, preferably M,

(xl) of Group ICa wherein R₁ is R_(1Cy), R₂ is R_(2Cy), R₃ is R_(3Cy), R₄ is R_(4Cy), R₁₇ is R'₁₇, R₁₈ is R'₁₈, and X is X',

(xli) of (xl) wherein R₁ is R'_(1Cy), R₂ is R'_(2Cy), R₃ is R'_(3Cy), R₄ is R'_(4Cy), R₁₇ is hydrogen, R₁₈ is R"₁₈, and X is (E)--CH═CH--,

(xlii) of (xli) wherein R₁ is R"_(1Cy), R₃ is R"_(3Cy), R₄ is R"_(4Cy), and R₁₈ is R"'₁₈, preferably M,

(xliii)-(xlviii) of (xxxvii)-(xlii) wherein the hydroxy groups in the 3- and 5-positions of the group of Formula a have the erythro configuration,

(xlix) of Group ICb wherein R₁ is R_(1Cx), R₂ is R_(2Cx), R₃ is R_(3Cx), R₄ is R_(4Cx), R₁₇ is R'₁₇, and X is X',

(l) of (xlix) wherein R₁ is R'_(1Cx), R₂ is R'_(2Cx), R₃ is R'_(3Cx), R₄ is R'_(4Cx), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(li) of (l) wherein R₂ is R"_(2Cx), R₃ is R"_(3Cx), and R₄ is methyl,

(lii) of Group ICb wherein R₁ is R_(1Cy), R₂ is R_(2Cy), R₃ is R_(3Cy), R₄ is R_(4Cy), R₁₇ is R'₁₇, and X is X',

(liii) of (lii) wherein R₁ is R'_(1Cy), R₂ is R'_(2Cy), R₃ is R'_(3Cy), R₄ is R'_(4Cy), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(liv) of (liii) wherein R₁ is R"_(1Cy), R₃ is R"_(3Cy), and R₄ is R"_(4Cy), and

(lv)-(lx) of (xlix)-(liv) wherein R₁₇ and the hydrogen atom in the 6-position of the group of Formula b are trans to each other, i.e., the trans lactones.

Groups (x)-(xviii) and (xliii)-(xlviii) embrace the 3R,5S-3S,5R racemate and the 3R,5S and 3S,5R enantiomers of the compounds wherein X is --CH═CH--, the 3S,5R enantiomer being least preferred, and the 3R,5R-3S,5S racemate and the 3R,5R and 3S,5S enantiomers of the compounds wherein X is --CH₂ CH₂ --, the 3S,5S enantiomer being least preferred.

Groups (xxviii)-(xxxvi) and (lv)--(lx) embrace the 4R,6S-4S,6R racemate and the 4R,6S and 4S,6R enantiomers of the compounds wherein X is --CH═CH--, the 4S,6R enantiomer being least preferred, and the 4R,6R-4S,6S racemate and the 4R,6R and 4S,6S enantiomers of the compounds wherein X is --CH₂ CH₂ --, the 4S,6S enantiomer being least preferred.

Other representative groups of compounds are (1)-(3) those of Formulae I, IB and IC wherein each of R₆, R₉, R₁₂ and R₁₅ is other than bromo and (4)-(23) those of Groups (i), (iv), (vii), (x), (xiii), (xvi), (xix), (xxii), (xxv), (xxviii), (xxxi), (xxxiv), (xxxvii), (xl), (xliii), (xlvi), (xlix), (lii), (lv) and (lviii) wherein each of R₆, R₉, R₁₂ and R₁₅ is other than bromo.

The compounds of Formula I may be synthesized as follows:

Reaction Scheme I

The compounds of Formula I wherein X is --(CH₂)_(m) -- or (E)--CH═CH--, and Z is a group of Formula a wherein R₁₇ is hydrogen, and R₁₈ is R'₁₉ or R₁₇ is R_(17a) and R₁₈ is M₂.sup.⊕ or R₂₀ may be synthesized by the following series of reactions: ##STR15##

Reaction Scheme II

The compounds of Formula I wherein X is --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, and Z is a group of Formula a wherein R₁₈ is R'₁₉ may be synthesized by the following series of reactions: ##STR16##

Reaction Scheme III

The compounds of Formula I wherein X is --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula b having the 4R,6S configuration or X is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, and Z is a group of Formula b having the 4R,6R configuration may be synthesized by the following series of reactions: ##STR17##

Reaction Scheme I

The compounds of Formula I wherein Z is a group of Formula a wherein R₁₈ is R'₁₉ or a group of Formula b may be converted into the corresponding compounds of Formula I wherein Z has a different significance by the following series of reactions: ##STR18##

Reaction Scheme V

The compounds of Formula VI may be synthesized by the following series of reactions: ##STR19##

Reaction Scheme VI

The compounds of Formulae XIX and XX may be synthesized by the following series of reactions: ##STR20##

Reaction Scheme VII

The compounds of Formula XLI wherein Pr is PrB wherein R₄ is R_(4a) may be synthesized by the following series of reactions: ##STR21##

In the preceding reaction schemes, ##STR22## wherein R₁ -R₄ are as defined above, ##STR23## wherein R₁ -R₄ are as defined above, and

R_(4a) and R₂₀ are as defined below, ##STR24## wherein R₁ -R₄ as defined above, and

R_(4a) and R₃₄ -R₃₆ are as defined below,

R_(4a) is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl ##STR25## wherein R₁₄ -R₁₆ are as defined above, R_(17a) is C₁₋₃ alkyl,

each R₂₀ is independently C₁₋₃ alkyl, preferably n-C₁₋₃ alkyl, and most preferably C₁₋₂ alkyl,

each R₂₁ is independently C₁₋₂ alkyl, the two C₁₋₂ alkyl groups preferably being the same,

each of R₃₄ and R₃₅ is independently C₁₋₆ alkyl not containing an asymmetric carbon atom, preferably methyl,

R₃₆ is C₁₋₆ alkyl not containing an asymmetric carbon atom, preferably methyl or t-butyl and especially t-butyl,

X₁ is --(CH₂)_(m) -- or (E)--CH═CH--, especially (E)--CH═CH--, wherein m is 0, 1, 2 or 3,

X₂ is --CH₂ -- or --CH₂ CH₂ --,

X₃ is a direct bond or --CH₂ --,

X₄ is --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, preferably (E)--CH═CH--, (E)--CH═CH--CH₂ -- or (E)--CH₂ --CH═CH-- and especially (E)--CH═CH--,

X₅ is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, especially --CH₂ CH₂ --,

X₆ is --CH═CH-- or --CH₂ --CH═CH--, preferably --CH═CH-- and especially (E)--CH═CH--,

Y is chloro, bromo or iodo,

Y.sup.⊕ is chloride, bromide or iodide,

Y' is chloro or bromo,

Y'.sup.⊖ is chloride or bromide,

M₂.sup.⊕ is sodium or potassium, and

each of the other variables is as defined above.

    __________________________________________________________________________                                                              Inert                                                                          Atmos-                Reaction/Type                                                                          Reagents, Molar Ratios and Comments                                                                  Temperature                                                                              Time    Solvent  phere                 __________________________________________________________________________     A       (1) Generation of dianion of VII:                                                                    -50°-10° C.,                                                               0.5-3 hrs.                                                                             AIO, e.g.,                                                                              Yes                           2-2.4 equivalents strong base,                                                                       pref. -20°-5° C.                                                                   pref. THF                                                                               (pref.                        pref. 1-1.1 moles sodium hydride then            argon)                        1-1.1 moles  -n-butyllithium or 2-2.2 moles                                    lithium diisopropylamide per mole VII.                                         (2) 1-2.5 moles, pref. 1.2-2.2 moles, more                                                           -80°-0° C.,                                                                0.2-4 hrs.,                                                                            Same as Step                                                                            Yes                           pref. 1.3-2.1 moles, dianion of VII                                                                  -50°-0° C.,                                                                pref. 0.3-       (pref.                        (assuming 100% conversion of VII to its                                                              pref. -30°-                                                                       2.5 hrs.         argon)                        dianion) per mole VI. When Pr is PrC                                                                 -10° C.                                           wherein R.sub.4 is hydrogen, use extra equiva-                                 lent of dianion, i.e., 2-3.5 moles, pref.                                      2.2-3.2 moles and more pref. 2.3-3.1                                           moles, per mole VI.                                                            (3) Quench with, e.g., saturated ammonium                                                            Same as Step 2                                                                           1-5 min.                                                                               Same as Step                                                                            --                            chloride solution.                                                             Product (VIII) is racemic.                                             B (Reduction)                                                                          (a) Non-stereoselective: 1-4, pref. 2-4,                                                             -10°-30° C.                                                                1-8 hrs.                                                                               IO, e.g.,                                                                               Yes                           equivalents transferable hydride per    lower alkanol,                         mole VIII, pref. sodium borohydride or  esp. ethanol                           complex of  .sub.- t-butylamine and borane. When                               a racemic VIII is utilized, product                                            (IX) is a mixture of all four possible                                         stereoisomers (the erythro and threo                                           racemates) wherein the ratio of the                                            erythro stereoisomers to the threo stereo-                                     isomers is about 3:2-2:3.                                                      (b) Stereoselective:                                                           (1) 1-2.2 moles, pref. 1.02-2 moles, tri-                                                            0°-50° C., pref.                                                           0.5-6 hrs.,                                                                            AIO, pref.                                                                              Pref.                         (primary or secondary C.sub.2-4 alkyl)-                                                              0°-25° C.                                                                  pref. 1-3.5                                                                            esp. THF,                                                                               Yes                           borane, pref. triethylborane or tri= -n-                                                                       hrs.    mixture of THF                         butylborane, and, optionally, air,      and methanol,                          e.g., 0.5-8 1., pref. 0.75-6.5 1.,      pref. a 3-4:1                          (at 25° C. and 760 mm. Hg.) per mole                                                                            mixture                                VIII.                                                                          (2) 0.4-10 moles, pref. 1-10 moles, sodium                                                           -100°--10° C.,                                                             1-96 hrs.,                                                                             Same as Step                                                                            Pref.                         borohydride per mole VIII. After the                                                                 pref. -90°-                                                                       pref. 12-72      Yes                           reaction, quench reaction mixture                                                                    -70° C.                                                                           hrs.                                           with, for example, 10% hydrochloric                                            acid and isolate crude product                                                 by extracting with a suitable inert                                            organic solvent (e.g., diethyl ether)                                          and evaporating the solvent at reduced                                         pressure. It is pref. to crystallize                                           the cyclic boron ester, if possible.                                           It may be necessary to complete the                                            reaction at -50°--10° C.                                         (3) Large excess of anhydrous methanol,                                                              20°-60° C.                                                                 0.5-5 hrs.,                                                                            Neat     --                            e.g., 50-100 moles per mole VIII. It                                                                           pref. 1-4                                      is convenient to azeotrope a solution                                                                          hrs.                                           of the product of Step 2 in methanol                                           three to four times.                                                           When a racemic VIII is utilized in Alter-                                      native b, product (IX) is a mixture of the                                     four possible stereoisomers wherein the                                        ratio of the erythro isomers (racemate) to                                     the threo isomers (racemate) is about 2-20:1,                                  usually 5-15:1, when the solvent is THF.                                       Repeated recrystallization of the cyclic                                       boron ester produced in Step 2 of Alternative                                  b, if a solid, may raise the ratio or even                                     yield pure erythro racemate and mother                                         liquors enriched with threo racemate. When,                                    however, the solvent is a mixture of                                           THF and methanol, said ratio may be as high                                    as 50-100:1.                                                           C       (1) Generation of monoanion of X: 1-1.1                                                              -80°--40° C.,                                                              0.25-1.5                                                                               AIO, e.g.,                                                                              Yes                           equivalents strong base, pref. lithium                                                               pref. -80°-                                                                       hrs.    pref. THF                              diisopropylamide, per mole X.                                                                        -75° C.                                           (2) 1-4 moles, pref. 3 moles, monoanion of                                                           -80°--40° C.,                                                              0.25-1.5                                                                               Same as Step                                                                            Yes                           X (assuming 100% conversion of X to its                                                              pref. -80°-                                                                       hrs.                                           monoanion) per mole VI. When Pr is PrC                                                               -75° C.                                           wherein R.sub.4 is hydrogen, use extra equiva-                                 lent of monoanion, i.e., 2-5 moles, pref.                                      4 moles, monoanion per mole VI.                                                (3) Quench with, for example, saturated                                                              -80°-25° C.                                                                1-5 min.                                                                               --       --                            ammonium chloride solution.                                                    Product (XI) is a racemate.                                            D (Acylation)                                                                          1-3 moles, pref. 2 moles, XII or XIII per                                                            -10°-50° C.,                                                               2-18 hrs.,                                                                             Pyridine                                                                                Yes                           mole XI. When an ES is used as the solvent,                                                          pref. 20-30° C.                                                                   pref. 4-12                                                                             anhydrous ES,                          also use 1-4 moles, pref. 2.5-3 moles, of a                                                                    hrs.    pref. THF                              tertiary amine, e.g., pyridine or, pref.,                                      4-dimethylaminopyridine, per mole XI. When                                     Pr is PrC wherein R.sub.4 is hydrogen, use extra                               equivalent of XII or XIII and tertiary amine                                   (when used), e.g., 2-4 moles, pref. 3 moles,                                   XII or XIII per mole XI. Always use at least                                   one mole of tertiary amine (when used) per                                     mole XII or XIII.                                                      E       (1) Generation of monoanion of XV: 1-1.1                                                             -80°-0° C.                                                                 0.25-1 hr.                                                                             AIO, e.g.,                                                                              Yes                           equivalents strong base, pref. lithium  pref. THF                              diisopropylamide, per mole XV.                                                 (2) 1-4 moles, pref. 3 moles, monoanion of                                                           -80°--40° C.,                                                              0.25-1.5                                                                               Same as Step                                                                            Yes                           XV (assuming 100% conversion of XV to its                                                            pref. -80°-                                                                       hrs.                                           monoanion) per mole XIV.                                                                             -70° C.                                           (3) Quench with, for example, saturated                                                              -80°-25° C.                                                                1-5 min.                                                                               --       --                            ammonium chloride solution.                                            F (Hydrolysis)                                                                         2-2.3 moles, pref. 2-2.2 moles, XVII per                                                             20° C.-reflux,                                                                    2-12 hrs.                                                                              Inert aqueous                                                                           --                            mole XVI. When Pr' contains an R.sub.20 --CO--                                                       pref. 20°-75° C.,                                                          when Pr'                                                                               organic, e.g.,                         group, utilize at least one additional                                                               esp. 50°-75° C.,                                                           contains                                                                               mixture of                             equivalent of XVII, e.g., 3-3.3 moles, pref.                                                         when Pr' con-                                                                            an R.sub.20 --CO--                                                                     water and lower                        3-3.2 moles, XVII per mole XVI.                                                                      tains an R.sub.20 --CO--                                                                 group and,                                                                             alkanol, pref.                                               group and,                                                                               otherwise,                                                                             mixture of                                                   otherwise,                                                                               1-4 hrs.                                                                               water and                                                    0° C.-reflux,                                                                             methanol or,                                                 pref. 0°-75° C.,                                                                   esp., ethanol                                                esp. 20°-50° C.                    G (Silylation)                                                                         1-3 moles II per mole XI. When Pr is PrC                                                             20°-30° C.,                                                                6-18 hrs.                                                                              Dry dimethyl-                                                                           Yes                           wherein R.sub.4 is hydrogen, use at least one                                                        20°-25° C.                                                                         formamide                              extra equivalent of II, e.g., 2-4 moles II                                     per mole XI. In either case, also use 1-2                                      moles triethylamine and catalytic amount of                                    imidazole or 1.1-2 moles imidazole                                             per mole II.                                                           H       Same as Reaction E (Molar quantities in                                                              Same as E Same as E                                                                              Same as                                                                                 Yes                           Step 2 are per mole III).                                              HA (Deprotec-                                                                          Same as Reaction J (Molar quantities are per                                                         Same as J Same as J                                                                              Same as                                                                                 --                    tion)   mole IV) when Pr" contains an --SiR.sub.34 R.sub.35 R.sub.36                   group. When Pr" does not contain an                                            --SiR.sub.34 R.sub.35 R.sub.36 group, utilize 1-4 moles, pref.                 2-4 moles, fluoride reagent per mole IV.                               I (Wittig)                                                                             Alternative a:                                                                 1) 1-2 moles strong base, e.g., sodium                                                               -40°-5° C.,                                                                5-60 min.                                                                              AIO, e.g.,                                                                              Yes                           hydride or pref.  -n-butyllithium, per                                                               -35°--20° C.                                                                       such as toluene                        mole XIX. Pref., slowly add  -n-butyl-  or, pref., ES                          lithium solution to solution of XIX.    such as THF                            When Pr is PrC wherein R.sub.4 is hydrogen, use                                2-3 moles strong base per mole XIX.                                            2) 0.65-1.5 moles XXI per mole XIX used in                                                           -55°-25° C.,                                                               0.75-18 Same as Step                                                                            Yes                           Step 1.               pref. -35°-                                                                       hrs., pref.                                                          -5° C.                                                                            1-4 hrs.                                       Alternative b:                                                                 1) 1 mole strong base, pref.  -n-butyllithium                                                        -10°-0° C.                                                                 1-1.5 hrs.                                                                             AIO, pref.                                                                              Yes                           or lithium diisopropylamide, and, option-                                                                              esp. THF                               ally, 1.75-2 moles lithium chloride per                                        mole XX. When Pr is PrC wherein R.sub.4 is                                     hydrogen, use extra equivalent of strong                                       base, i.e., 2 moles per mole XX. Add                                           strong base to other reactants.                                                (2) 1-1.2 moles XXI per mole XX used                                                                 -10°-0° C.                                                                 1-12 hrs.                                                                              Same as Step                                                                            Yes                           in Step 1.                                                                     Product (XXII) is a mixture of the (Z)                                         and (E) (cis and trans, respectively)                                          isomers which may be separated by chroma-                                      tography. The (E) to (Z) ratio may be                                          higher with Alternative b than                                                 with Alternative a.                                                    J (Deprotec-                                                                           2-8 moles, pref. 4-8 moles, fluoride reagent,                                                        20°-60° C.,                                                                2-30 hrs.                                                                              AIO, e.g.,                                                                              --,                   tion)   esp. tetra- -n-butylammonium fluoride, per                                                           20°-25° C.                                                                         pref. THF                              mole XXII and 1-2 moles, pref. 1.2-1.5 moles,                                  glacial acetic acid per mole fluoride                                          reagent. First add glacial acetic acid to                                      solution of XXII, then add fluoride reagent.                           K (Hydrogena-                                                                          Excess hydrogen (more than 1 mole per mole                                                           20°-25° C.                                                                 Until 1 Lower alkanol,                                                                          --                    tion)   XXII) and catalytic amount of platinum                                                                         mole    e.g., ethanol                          dioxide (e.g., 1-5 g. per mole XXII). Ini-                                                                     hydrogen                                       tial hydrogen pressure is conveniently 30-60                                                                   per mole                                       p.s.i.                          XXII is                                                                        taken up                               L (Deprotec-                                                                           Same as Reaction J (Molar quantites are                                                              Same as J Same as J                                                                              Same as                                                                                 --                    tion)   per mole XXIV).                                                        M (Wittig)                                                                             Same as Reaction I. (Reactant in Step 2                                                              Same as I Same as I                                                                              Same as                                                                                 Yes                           is XXVI). Product (XXVII) is a mixture of                                      the (Z) and (E) (cis and trans, respectively)                                  isomers which may be separated by                                              chromatography. The (E) to (Z) ratio may                                       be higher with Alternative b than                                              with Alternative a.                                                    N (Deprotec-                                                                           Same as Reaction J except utilize 1-4 moles,                                                         Same as J Same as J                                                                              Same as                                                                                 --                    tion)   pref. 2-4 moles, fluoride reagent per mole                                     XXVII.                                                                 O (Hydrogena-                                                                          Same as Reaction K (Molar quantities are                                                             Same as K Same as K                                                                              Same as                                                                                 --                    tion)   per mole XXVII).                                                       P (Deprotec-                                                                           Same as Reaction J except utilize 1-4 moles,                                                         Same as J Same as J                                                                              Same as                                                                                 --                    tion)   pref. 2-4 moles, fluoride reagent per mole                                     XXIX.                                                                  Q (Hydrolysis)                                                                         1-1.3 equivalents XVII per mole XXXI or, if                                                          0° C.-reflux,                                                                     1-4 hrs.                                                                               Inert aqueous                                                                           --                            it is desired to isolate XXXII, 0.92-0.99                                                            pref. 0°-75° C.,                                                                   organic, e.g.,                         equivalent XVII per mole XXXI.                                                                       esp. 20°-70° C.                                                                    mixture of                                                                     water and lower                                                                alkanol, pref.                                                                 mixture of                                                                     water and                                                                      methanol or,                                                                   esp., ethanol                  R (Acidifica-                                                                          At least 1 equivalent, e.g., 1-1.25 equiv-                                                           0°-25° C.                                                                  1-5 min.                                                                               Water or                                                                                --x-                  tion)   alents, acid, e.g., 2N.hydrochloric acid,                                                                              ture of water                          per mole XXXII.                         and water-                                                                     miscible or                                                                    partially                                                                      miscible inert                                                                 organic sol-                                                                   vent, e.g.,                                                                    methanol,                                                                      ethanol,                                                                       diethyl ether                                                                  or THF                         S (Neutraliza-                                                                         0.95-0.99 equivalent, pref. 0.96-0.98                                                                0°-25° C., pref.                                                           2-10 min.                                                                              Same as                                                                                 --                    tion)   equivalent, XXXIV per mole XXXIII.                                                                   20°-25° C.                         T (Lactoniza-                                                                          Alternative a:                                                         tion)   Use of catalytic amount of strong acid                                                               75° C.-reflux,                                                                    3-18 hrs.,                                                                             AIO, pref.                                                                              --,                           such as  -p-toluenesulfonic acid is optional                                                         pref. 75°-                                                                        pref. 4-7                                                                              e.g., benzene,                         but usually omit. Use of Dean-Stark                                                                  150° C., esp.                                                                     hrs.    toluene or                             apparatus is pref. if solvent forms                                                                  80°-120° C.                                                                        xylene or                              azeotrope with water.                   mixture                                                                        thereof                                Alternative b:                                                                 1-1.5 moles of a lactonization agent,                                                                10°-35° C.,                                                                2-8 hrs.,                                                                              AIO, pref.                                                                              --                            e.g., a carbodiimide, pref. a water-                                                                 20°-25° C.                                                                 pref. 3-4                                                                              HLA, esp.                              soluble carbodiimide such as N-cyclo-                                                                          hrs.    methylene                              hexyl-N'-[2'-(N"-methylmorpholinium)-   chloride                               ethyl]carbodiimide  -p-toluenesulfonate,                                       per mole XXXIII.                                                               Alternative b often results in higher yields                                   of XXXVI than Alternative a. Racemic                                           erythro XXXIII yields racemic trans (lactone)                                  XXXVI, racemic threo XXXIII yields                                             racemic cis (lactone) XXXVI, mixture of                                        racemic erythro and threo XXXIII yields                                        mixture of racemic trans and cis (lactones)                                    XXXVI, and single enantiomer of XXXIII                                         yields single enantiomer of XXXVI,                                             e.g., 3R,5S erythro XXXIII yields                                              4R,6S trans XXXVI.                                                     U (Esterifica-                                                                         At least 2 moles, e.g., 2-10 moles, pref.                                                            0°-70° C., pref.                                                           2-12 hrs.                                                                              IO, e.g.,                                                                               --                    tion)   2.05-2.5 moles, XXXVII per mole XXXVI.                                                               20°-25° C.                                                                         such as THF or                         See comment concerning Reaction V, this alcohol of the                         column.                                 formula R.sub.19 --OH                                                          (R.sub.19 same as                                                              in XXXVII), if                                                                 a liquid                       V (Hydrolysis)                                                                         1-1.3 equivalents XVII per mole XXXVI or,                                                            0° C.-reflux,                                                                     1-6 hrs.,                                                                              Same as                                                                                 --                            if it is desired to isolate XXXII, 0.95-1                                                            pref. 0°-75° C.,                                                           pref. 1-4                                      equivalent, preferably 0.97-0.99 equivalent,                                                         more pref. 20°-                                                                   hrs.                                           XVII per mole XXXVI.  75° C., esp. 40°-                          Racemic trans (lactone) XXXVI yields                                                                 60° C.                                            racemic erythro XXXII or XXXVIII,                                              racemic cis (lactone) XXXVI yields                                             racemic threo XXXII or XXXVIII,                                                mixture of racemic trans and                                                   cis (lactones) XXXVI yields mixture of                                         racemic erythro and threo XXXII or                                             XXXVIII, and single enantiomer of XXXVI                                        yields single enantiomer of XXXII or                                           XXXVIII, e.g., 4R,6S trans XXXVI                                               yields 3R,5S erythro XXXII or XXXVIII.                                 AA (Reduction)                                                                         0.5-3.2 moles, pref. 0.75-3 moles, lithium                                                           -5°-25° C.,                                                                2-6 hrs.,                                                                              AIO, e.g.,                                                                              Yes                           aluminum hydride per mole XLI. Pref.                                                                 pref. -5°-5° C.                                                            pref. 2-4                                                                              pref. THF or                           commence at -5°-5° C. and allow reaction                                               20°-25° C. or                                                              hrs.    diethyl ether                          mixture to warm to 20°-25° C. as reaction                                              0°-5° C.                                   proceeds or run entire reaction at 0°-5° C.              AB (Oxidation)                                                                         1-3.5 moles, pref. 1.2-3 moles, pyridinium                                                           20°-30° C.,                                                                2-18 hrs.,                                                                             AIO, pref.                                                                              Yes,                          chlorochromate or pyridinium dichromate,                                                             20°-25° C.                                                                 pref. 3-12                                                                             esp. methylene                         5-10 moles, pref. 6-8 moles, chromium                                                                          hrs., with                                                                             chloride, for                          trioxide (pref. complexed with pyridine,                                                                       pyridinium                                                                             pyridinium                             more pref. 2 moles pyridine per mole chrom-                                                                    chloro- chlorochromate,                        ium trioxide), 5-50 moles, pref. 10-20                                                                         chromate or                                                                            chromium                               moles, manganese dioxide, pref. activated                                                                      chromium                                                                               trioxide or                            manganese dioxide, or, pref., 2-4 moles                                                                        trioxide,                                                                              pyridinium                             N-methylmorpholine-N-oxide.mono-                                                                               8-24 hrs.,                                                                             dichromate and                         hydrate and catalytic amount (e.g.,                                                                            pref. 15-                                                                              pref. HLA or                           0.02-0.05 mole) tris(triphenyl- 18 hrs.,                                                                               ES, esp.                               phosphine)ruthenium (II) chloride (CXI),                                                                       with pyri-                                                                             diethyl ether,                         per mole XLII.                  dinium  for manganese                                                          dichromate,                                                                            dioxide and                                                            4-48 hrs.,                                                                             dry acetone                                                            pref.   for N-methyl-                                                          10-24 hrs.,                                                                            morpholine-                                                            with    N-oxide.                                                               manganese                                                                              monohydrate                                                            dioxide                                                                        and 1-5                                                                        hrs. with                                                                      N-methyl-                                                                      morpholine-                                                                    N-oxide.                                                                       monohydrate                            AC (Wittig)                                                                            (1) Synthesis of ylide: 1-1.05 moles strong                                                          -40°-0° C.,                                                                1-4 hrs.                                                                               AIO, pref.                                                                              Yes                           base, e.g., sodium hydride, phenyllithium                                                            pref. -35°-                                                                               e.g., THF                              or, pref.,  -n-butyllithium per mole XLIV.                                                           -20° C.                                           Pref., slowly add solution of strong                                           base to solution of XLIV.                                                      (2) Synthesis of enol ether: Ylide from                                                              -30°-0° C.,                                                                1-4 hrs.                                                                               Same as Step                                                                            Yes                           1-1.05 moles XLIV per mole XLIII.                                                                    pref. -20 -0° C.                                  (3) Hydrolysis of enol ether: Large molar                                                            0°-30° C.                                                                  8-24 hrs.                                                                              Mixture                                                                                 --                            excess, e.g., 2-20 moles, strong acid,  aqueous acid                           e.g., 70% perchloric acid, per mole XLIII                                                                              and ES, e.g.,                          used in Step 2.                         mixture of 70%                                                                 perchloric                                                                     acid and THF                   AD (Wittig)                                                                            Same as Reaction AC (Molar quantities in                                                             Same as AC                                                                               Same as AC                                                                             Same as                                                                                 Same as                       Steps 2 and 3 are per mole XLV).                 AC                    AE (Wittig)                                                                            Same as Reaction AC (Molar quantities in                                                             Same as AC                                                                               Same as AC                                                                             Same as                                                                                 Same as                       Steps 2 and 3 are per mole XLVI).                AC                    AF (Wittig)                                                                            Alternative a:                                                                 1-2 moles, pref. 1-1.7 moles, XLVIII per                                                             80° C.-reflux,                                                                    6-18 hrs.                                                                              AIO, pref.                                                                              Yes                           mole XLIII.           esp. refluxing    esp. toluene                                                 toluene                                                  Alternative b:                                                                 (1) Synthesis of ylide: 1-1.07 moles strong                                                          -20°-25° C.,                                                               0.75-2 hrs.                                                                            AIO, pref.                                                                              Yes                           base, pref. sodium hydride, per mole                                                                 pref. -20°-0° C.                                                                   esp. THF                               XLIX. Pref., add small amount of XLIX                                          to suspension of sodium hydride in THF                                         stirred at 20°-25° C., cool to -20°--15.degre             e. C.                                                                          once reaction commences and complete                                           reaction at -20°--15° C.                                         (2) 1-1.6 moles ylide from XLIX (assuming                                                            -20°-65° C.                                                                0.75-20 Same as Step                                                                            Yes                           100% conversion of XLIX to ylide) per                                                                          hrs.                                           mole XLIII. Pref., add solution of XLIII                                       to ylide solution at -20°--15° C., stir                          at -20°--25° C. for balance of reaction                          and, if necessary, complete reaction at                                        40°-65° C.                                               AG (Reduc-                                                                             (1) At least 2 equivalents transferable                                                              -78 °-25° C.,                                                              0.7-3 hrs.                                                                             AIO, pref.                                                                              Yes                   tion)   hydride from a metal hydride reducing                                                                pref.             e.g., THF                              agent, e.g., lithium aluminum hydride                                                                -78°--20° C.                               or diisobutylaluminum hydride, per mole                                        L, pref. 3.8-6 moles diisobutylaluminum                                        hydride per mole L.                                                            (2) Quench with, for example, water or                                                               -78°-25° C.                                                                5-15 min.                                                                              --       --                            saturated ammonium chloride or sodium                                          sulfate solution.                                                      AH (Oxidation)                                                                         5-50 moles, pref. 10-30 moles, manganese                                                             20° C.-reflux,                                                                    3-24 hrs.,                                                                             AIO, pref.                                                                              Yes                           dioxide, pref. activated manganese dioxide,                                                          pref. 20°-40° C.                                                           pref. 10-                                                                              or ES, esp.                                                                             with N-                       or, pref., 2-4 moles N-methylmorpholine-N-                                                           with manganese                                                                           18 hrs. diethyl                                                                                 methyl-                       oxide.monohydrate and catalytic amount                                                               dioxide and       with manganese                                                                          morpho-                       (e.g., 0.02-0.05 mole) CXI, per mole LI.                                                             20°-25° C. with                                                                    dioxide                                                                                 line-                                               N-methyl-         dry acetone                                                                             N-oxide.                                            morpholine-       with N-methyl-                                                                          mono-                                               N-oxide.          morpholine-                                                                             hydrate                                             monohydrate       N-oxide.                                                                       monohydrate                    AI      (p) Preparation of LIII: 2-2.1 moles, pref.                                                          -80°--75° C.,                                                              1-5 hrs.,                                                                              AIO, e.g.,                                                                              Yes                           2 moles,  .sub.- t-butyllithium, pref. as 1-2M.                                                      pref. -78° C.                                                                     pref. 2-4                                                                              pref. THF                              solution in pentane, per mole cis-1-bromo-                                                                     hrs.                                           2-ethoxyethylene.                                                              (1) 1-1.75 moles LIII (assuming 100% yield                                                           -80°--40° C.,                                                              0.75-8 hrs.                                                                            Same as Step                                                                            Yes                           from Step p) per mole XLIII. When Pr                                                                 pref. -80°-                                                                       pref. 1-                                       is PrC wherein R.sub.4 is hydrogen, utilize                                                          -60° C.                                                                           4 hrs.                                         an extra equivalent of LIII, i.e., 2-                                          2.75 moles LIII per mole XLIII. When it                                        is desired to isolate and/or purify the                                        crude enol ether intermediate, quench the                                      reaction mixture with, e.g., saturated                                         ammonium chloride solution at -80°-25° C.                        for 1-5 min. Otherwise, quenching is                                           optional since it will occur at the                                            beginning of Step 2. Crude enol ether                                          product of this step may be used in next                                       step without isolation and purification                                        but isolation and purification of enol                                         ether intermediate may improve yield of                                        LII from next step.                                                    (Hydrolysis)                                                                           (2) Catalytic amount of  -p-toluenesulfonic                                                          20°-40° C.,                                                                0.5-5 hrs.,                                                                            Mixture of                                                                              --                            acid or monohydrate thereof (e.g., 0.5-                                                              20°-25° C.                                                                 pref. 0.5-                                                                             and water,                             100 g., pref. 1-5 g., per mole XLIII                                                                           4 hrs.  pref. mixture                          used in Step 1) and water.              of THF and                                                                     water                          BA (Halogena-                                                                          1-2 moles, pref. 1.5-1.8 moles, LV or LVI                                                            -10°-80° C.                                                                2-18 hrs.                                                                              AIO, pref.                                                                              --,                   tion)   per mole XLII.                          e.g., diethyl                                                                  ether or THF,                                                                  HLA, e.g.,                                                                     methylene                                                                      chloride, or                                                                   HC, e.g.,                                                                      benzene                        BB      Excess triphenylphosphine, e.g., 2-10 moles                                                          60° C.-reflux,                                                                    0.5-24 hrs.                                                                            AIO, pref.                                                                              Yes                           per mole LVII.        pref. ≦150° C.,                                                                    absolute                                                     esp. 75°-78° C.                                                                    ethanol                                                      (in absolute                                                                   ethanol)                                         BC      1-1.1 moles LIX per mole LVII. Can use                                                               20°-140° C.,                                                               6-24 hrs.,                                                                             HC, e.g.,                                                                               Yes                           excess LIX as the solvent.                                                                           usually   usually benzene or                                                   110°-140° C.                                                               10-16 hrs.                                                                             xylene or neat                                                                 (excess LIX                                                                    is solvent)                    BD      Same as Reaction B, Alternative a (Molar                                                             Same as B, a                                                                             Same as B, a                                                                           Same as B,                                                                              Yes                           quantities are per mole XLV).                                          BE (Halogena-                                                                          Same as Reaction BA (Molar quantities are                                                            Same as BA                                                                               Same as BA                                                                             Same as                                                                                 --                    tion)   per mole LXI).                                                         BF      Same as Reaction BB (Molar quantities are                                                            Same as BB                                                                               Same as BB                                                                             Same as                                                                                 Yes                           per mole LXII).                                                        BG      Same as Reaction BC (Molar quantities are                                                            Same as BC                                                                               Same as BC                                                                             Same as                                                                                 Yes                           per mole LXII).                                                        Ca (Halogena-                                                                          1 mole LXVII per mole LXVI. In this reac-                                                            0°-40° C.                                                                  2-18 hrs.                                                                              AIO, pref.                                                                              --A,                  tion)   tion, LXVII is pref. Br.sub.2.          e.g., chloro-                                                                  form                           CB      1-2 moles triphenylphosphine                                                                         20°-40° C.,                                                                8-24 hrs.                                                                              AIO, pref.                                                                              Yes                           per mole LXVIII.      20°-25° C.                                                                         or HC, esp.                                                                    toluene                        CC (Wittig)                                                                            (1) 1-1.02 moles base, e.g., sodium ethoxide,                                                        20°-80° C.                                                                 0.25-4 hrs.                                                                            AIO, pref.                                                                              Yes                           per mole LXIX.                          lower alkanol,                                                                 esp. ethanol                           (2) 1-1.25 moles LXX per mole LXIX used in                                                           60°-80° C.                                                                 8-24 hrs.                                                                              Same as Step                                                                            Yes                           Step 1.                                                                CD      (1) 1-1.3 moles base, e.g., sodium hydroxide,                                                        20°-30° C.                                                                 5-15 min.                                                                              Mixture                                                                                 --                            per mole LXVI.                          lower alkanol,                                                                 pref. ethanol,                                                                 and water                              (2) 1-1.05 moles LXX per mole LXVI.                                                                  0°-5° C. →                                                          2-5 hrs.                                                                               Same as Step                                                                            --                            Add LXX at 0°-5° C. and allow to warm                                                  20°-25° C.                                 to 20°-25° C.                                            CE      (1) 1-1.08 moles strong base, pref. lithium                                                          -80°--60° C.,                                                              0.4-1 hr.                                                                              AIO, pref.                                                                              Yes                           diisopropylamide, per mole LXXII.                                                                    pref. -78° C.                                                                             esp. THF                               (2) 1-1.03 moles carbanion of LXXII (assuming                                                        Same as Step 1                                                                           2-5 hrs.                                                                               Same as Step                                                                            Yes                           100% conversion of LXXII to its carbanion)                                     per mole LXXI.                                                                 (3) Quench with, for example, saturated                                                              Same as Step 1                                                                           1-5 min.                                                                               Same as Step                                                                            --                            ammonium chloride solution.                                            CF      5.5-6.5 moles, pref. 6 moles, N-bromo-                                                               0° C.                                                                             3-6 hrs.                                                                               Mixture                                                                                 --                            succinimide per mole LXXIII.            acetonitrile                                                                   and water,                                                                     pref. a 4:1                                                                    mixture                        CG      1-4 moles, pref. 2-4 moles, LXXV and 0.4-1                                                           0°-120° C.,                                                                12-24 hrs.                                                                             AIO, pref.                                                                              Yes                           mole, pref. 0.6 mole, titanium tetrachloride                                                         pref. 0° →                                                                         esp. mixture                           per mole LXXIV. Pref., combine reactants                                                             111° C.    of hexane and                          at 0° C., allow to warm to 20°-25° C. and                 heat                                    toluene                                at 100°-120° C. for 10-22 hrs., e.g., reflux                     in toluene for 16 hrs.                                                 __________________________________________________________________________      In the preceding table,                                                        AIO = anhydrous inert organic solvent                                          ES = ether solvent, for example, diethyl ether, 1,2diethoxyethane,             1,2dimethoxyethane, tetrahydrofuran and mixtures thereof                       esp. = especially                                                              HC = hydrocarbon solvent, for example, benzene, toluene, xylene and            mixtures thereof                                                               HLA = halogenated lower alkane solvent, for example, carbon tetrachloride      chloroform, 1,1dichlorethane, 1,2dichloroethane, methylene chloride and        1,1,2trichloroethane, usually preferably methylene chloride                    hr. (hrs.) = hour(s)                                                           IO = inert organic solvent                                                     min. = minutes                                                                 pref. = preferably, preferred                                                  THF = tetrahydrofuran                                                    

Most of the molar amounts (ratios) given in the preceding table are merely exemplary and may be varied, as is evident to one of ordinary skill in the art. For example, in a reaction of two compounds one of which is readily available and one of which isn't, an excess of the readily available compound may be used to drive the reaction further towards completion (unless the use of an excess would increase the synthesis of an undesired compound).

Likewise, most of the temperature ranges given in the preceding table are merely exemplary, and it is within the ability of one of ordinary skill in the art to vary those that are not critical.

The reaction times set forth in the preceding table are also merely exemplary and may be varied. As is well known, the reaction time is often inversely related to the reaction temperature. Generally, each reaction is monitored by, for example, thin layer chromatography and is terminated when at least one starting material is no longer present, when it appears that no more of the desired product is being formed, etc.

Conventional work-up procedures have generally been omitted from the preceding table.

As utilized in the preceding table, the term "solvent" embraces mixtures of solvents and implies that the reaction medium is a liquid at the desired reaction temperature. It should, therefore, be understood that not all of the solvents listed for a particular reaction may be utilized for the entire recited temperature range. It should also be understood that the solvent must be at least substantially inert to the reactants employed, intermediates generated and end products under the reaction conditions utilized.

The term "inert atmosphere", as utilized in the preceding table, means an atmosphere that does not react with any of the reactants, intermediates or end products or otherwise interfere with the reaction. While a carbon dioxide atmosphere is suitable for certain reactions, the inert atmosphere is usually nitrogen, helium, neon, argon or krypton, or a mixture thereof, and most often dry nitrogen to maintain anhydrous conditions. Most reactions, including those where the use of an inert atmosphere is not specified, are carried out under an inert atmosphere, usually dry nitrogen, for convenience.

In the preceding table, n-butyllithium is preferably employed as a 1.3-1.7M. solution in hexane, and lithium diisopropylamide is preferably prepared in situ from n-butyllithium and diisopropylamine.

Reactions analogous to Reactions A-J, L-N, P-V, AA-AH, BA, BB, BD-BF and CB are described in detail in copending application Ser. No. 06/722,288, filed by Faizulla G. Kathawala on Apr. 11, 1985 and titled Indole Analogs Of Mevalonolactone And Derivatives Thereof. These reactions may be carried out analogously to the corresponding reactions of said application. Said application is hereby incorporated by reference. Generally, where the reaction conditions set forth in said application differ from those set forth in this specification, the reaction conditions set forth in said application may also be utilized for the compounds of this specification.

The product of each reaction may, if desired, be purified by conventional techniques such as recrystallization (if a solid), column chromatography, preparative thin layer chromatography, gas chromatography (if sufficiently volatile), fractional distillation under high vacuum (if sufficiently volatile) or high pressure (performance) liquid chromatography (HPLC). Often, however, the crude product of one reaction may be employed in the following reaction without purification.

Some of the reactions described above may yield mixtures of two or more products only one of which leads to the desired compound of Formula I. Any obtained mixture may be separated by conventional techniques such as those set forth in the preceding paragraph.

As is evident to those in the art, each of the compounds of Formulae III, VIII, XI and XIV has a single center of asymmetry and, therefore, may be resolved into two optically active isomers. When a compound of Formula III, VIII or XIV is converted into a compound of Formula IV, IX or XVI, respectively, an additional center of asymmetry is generated. Consequently, when a racemic compound of Formula III, VIII or XIV is utilized, four stereoisomers (two pairs of diastereoisomers) of the resulting compound of Formula IV, IX or XVI are formed, whereas when an optically pure compound of Formula III, VIII or XIV is utilized, two diastereoisomers of the compound of Formula IV, IX or XVI are formed.

The compounds of Formulae I (including those of Formulae IB, IC, V, XVIII, XXIII, XXV, etc.), IV, XVI, XXI, XXII and XXIV have two centers of asymmetry and, therefore, may exist in four stereoisomeric forms. Except where the compound is formed from an optically pure precursor already having both chiral carbon atoms or where the reaction involves the use of a stereospecific reagent that gives an optically pure product, the compound is obtained as a mixture of two (if formed from an optically pure compound having one center of asymmetry) or four (if formed from a racemic compound having one center of asymmetry) stereoisomers.

The one or two centers of asymmetry of each compound of Formulae LXVIII, LXIX, LXXIII and LXXIV may be ignored since each center of asymmetry is destroyed in a following reaction (Reaction CG).

The obtained mixtures of stereoisomers may be separated by conventional means. For example, diastereoisomers may be separated by fractional crystallization, column chromatography, preparative thin layer chromatography and HPLC. Each mixture of four stereoisomers of a compound of Formula XXXVI may, for example, be separated by HPLC into its cis and trans (lactone) components, each of which is a racemate that may be resolved into two optically active enantiomers.

Techniques for separating a racemate into its two optically active enantiomers are known. For example, a racemic compound having a carboxylic acid group may be reacted with an optically pure organic base having at least one center of asymmetry to form a mixture of diastereoisomeric salts that may be separated by fractional crystallization, column chromatography, etc. or it may be reacted with an optically pure alcohol having at least one center of asymmetry to form a mixture of diastereoisomeric esters which may be separated by conventional techniques such as those set forth above or below. Likewise, a racemic compound having a carboxylic acid, acyl halide, ester or lactone group may be reacted with an optically pure organic base, i.e., an amine, to form a mixture of diastereoisomeric amides that may be separated by conventional means, e.g., fractional crystallization, column chromatography and/or HPLC. For example, a racemic lactone of Formula XXXVI may be reacted with an excess of R-(+)-α-methylbenzylamine (or the corresponding S-(-) compound) to form a mixture of two diastereoisomeric α-methylbenzylamides which may be separated by, for example, column chromatography on a silica gel column and/or by HPLC using a Partisil column. Often it is desirable to utilize both techniques, i.e., to partially separate the diastereoisomers by column chromatography and to purify each fraction by HPLC. Typically, the α-methylbenzylamides are synthesized by reacting the racemic lactone with a large molar excess of the amine at 20°-25° C. for 16-24 hours. The reaction is run neat, with the excess amine serving as the solvent. After the reaction, the excess amine is removed by vacuum distillation at 25°-35° C. After separation, each chiral amide may be hydrolyzed to the corresponding, for example, sodium, salt by, for example, refluxing with 1.5-3, preferably 2-2.2, equivalents of a base such as sodium hydroxide for 5-25 hours in a mixture of water and ethanol. The resulting salts may be converted to the corresponding free acids, esters, lactones and other salts by conventional means such as the reactions set forth in Reaction Scheme IV. On the other hand, a racemic compound having a hydroxy group may be esterified with an optically pure carboxylic acid having at least one center of asymmetry to form a mixture of diastereoisomeric esters or it may be reacted with an optically pure trisubstituted silyl halide, e.g., (-)-α-naphthylphenylmethylchlorosilane (Sommer et al., J. Am. Chem. Soc. 80, 3271 ( 1958).), to form a mixture of two diastereoisomeric silyloxy compounds, which mixture may be separated by conventional techniques. For example, diastereoisomeric (-)-α-naphthylphenylmethylsilyl derivatives of a lactone of Formula XXXVI may be separated on a silica column having covalently bound L-phenylglycine. After separation, the optically pure salts, amides, esters or silyloxy compounds are reconverted to the corresponding carboxy group- or hydroxy group-containing compounds with retention of optical purity. For example, the process conditions disclosed for Reactions J, L, N and P may be utilized to cleave (-)-α-naphthylphenylmethylsilyl and other silyl groups.

The compounds of Formulae II, VII, X, XII, XIII, XV, XVII, XXXIV, XXXVII, XLIV, XLVIII, XLIX, LIII, LV, LVI, LIX, LXVI-LXXII, LXXV and LXXVI and the reagents not designated by a Roman numeral are known or, if unknown, may be synthesized by processes analogous to those described in the literature for similar known compounds.

The compounds of Formula XLI are also either known or, if unknown, may be synthesized by processes analogous to those described in the literature for the known compounds of said formula and similar compounds. See, for example, Barton, Tetrahedron Letters 25, 3707-3710 (1984), McKinnon, Canadian J. Chem. 43, 2628-2631 (1965), Patterson, Synthesis 1976, . 281-304 and Sundberg, Comprehensive Heterocyclic Chemistry, The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds, Vol. 4, Part 3, Bird et al. ed., Pergamon Press, Oxford (1984), pp. 313-374, and the references cited in each which are hereby incorporated by reference. A synthesis of the compounds of Formula XLI useful for the synthesis of the preferred compounds of Formula I is described in Reaction Scheme VII.

A preferred process for the synthesis of the erythro racemate of the compound of Formula XXI wherein R₁₇ is hydrogen, R₁₉ ' is methyl, and X₃ is a direct bond is disclosed in Kapa, Tetrahedron Letters 25, 2435-2438 (1984). The other compounds of Formula XXI wherein R₁₇ is hydrogen, and X₃ is a direct bond in racemic erythro form may be synthesized similarly. See also U.S. Pat. No. 4,571,428. Said patent, particularly columns 3-11 thereof, is hereby incorporated by reference.

The compounds of Formulae XXI and XXVI and their synthesis are disclosed in U.S. Pat. No. 4,613,610. Said patent, particularly columns 19-24, 27-30 and 41-48 thereof, is hereby incorporated by reference.

Since any compound of Formula I wherein Z is a group of Formula a wherein R₁₈ is a cation other than M may be converted into the corresponding compound wherein R₁₈ is hydrogen, M or R₁₉ by the processes of Reaction Scheme IV, the compounds of Formula I wherein Z is a group of Formula a and R₁₈ is a pharmaceutically unacceptable cation are also within the scope of this invention since they are useful as intermediates. However, such compounds are not compounds of Formula I as utilized in this specification, except where indicated to the contrary.

Also within the scope of this invention are the intermediates of Formulae III, IV, VIII, XI, XIV, XVI, XIX, XX, XXII, XXIV, XXVII, XXIX, XLV-XLVII and L-LII. The preferences for each variable are the same as those set forth for the compounds of Formula I, with the preferred groups of such compounds including those that correspond to Groups (xix)-(xxxvi) and (xlix)-(lx) (for Formulae XXVII and XXIX) and Groups (i)-(xviii) and (xxxvii)-(xlviii) (for each of the others) to the extent consistent therewith.

The entire specification of abandoned grandparent application Ser. No. 06/791,198, particularly pages 1-15, 23, 26, 41-44 and 51-53 thereof, is hereby incorporated by reference as if set forth herein in its entirety.

Besides having the utility set forth below, every compound of Formula I is useful as an intermediate in the synthesis of one or more other compounds of Formula I utilizing the reactions set forth in Reaction Scheme IV.

The compounds of Formula I are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis, and, therefore, they are inhibitors of cholesterol biosynthesis. Consequently, they are useful for lowering the blood cholesterol level in animals, e.g., mammals, especially larger primates such as humans, and, therefore, as hypolipoproteinemic and anti-atherosclerotic agents. The biological activity of the compounds of Formula I may be demonstrated in the following two tests:

Test A. In Vitro Microsomal Assay of HMG-CoA Reductase Inhibition:

This test is carried out precisely as described in column 53 of U.S. Pat. No. 4,613,610 and on page 30 of World (PCT) Published Patent Application No. 84/02131, both of which are hereby incorporated by reference as if set forth herein in their entirety. The concentration of the test substance (compound of Formula I) in the assay system is 0.0005-2,000 μmolar. The obtained IC₅₀ is the concentration of the test substance in the assay system observed or calculated to produce a 50% inhibition of HMG-CoA reductase activity.

Test B. In Vivo Cholesterol Biosynthesis Inhibition Test:

This test is carried out precisely as described in column 53 of said U.S. Pat. No. 4,613,610 and on page 33 of World (PCT) Published Patent Application No. 84/02131, both of which are hereby incorporated by reference as if set forth herein in their entirety. In this test the rats are orally administered the test substance (compound of Formula I) at a dose of 0.1-200 mg/kg. body weight. The obtained ED₅₀ is the dose of the test substance observed or calculated to produce a 50% inhibition of 3β-hydroxysterol synthesis.

In Test A, tested compounds of Formula I had IC_(b) 50 's of 0.014-0.454 μmolar whereas that of Compactin was 1.1 μmolar and that of Mevinolin was 0.72 μmolar. The preferred compound of this application, that of Example 2, had an IC₅₀ of 0.014 μmolar. In Test B, tested compounds of Formula I had ED₅₀ 's of 0.53-0.97 mg./kg. whereas that of Compactin was 3.5 mg./kg. and that of Mevinolin was 0.41 mg./kg. The ED₅₀ of the preferred compound, that of Example 2, was 0.53 mg./kg.

Since they inhibit cholesterol biosynthesis, the compounds of Formula I (including those of each subgroup thereof) are useful for lowering the blood cholesterol level in animals, e.g., mammals, especially larger primates, in particular humans, and, therefore, as hypolipoproteinemic and anti-atherosclerotic agents.

The precise dosage of the compound of Formula I to be employed for inhibiting cholesterol biosynthesis depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration and the particular active substance (compound of Formula I) employed. However, in general, suitable oral daily dosages of the compounds of Formula I for the satisfactory inhibition or reduction of cholesterol biosynthesis (i.e., the satisfactory reduction of blood cholesterol level and satisfactory treatment of hyperlipoproteinemia and atherosclerosis) are indicated by the test data to be 0.06-100 mg./kg. body weight, e.g., 0.06-6 mg./kg. body weight for the more active compounds. For most larger primates such as humans, a suitable oral daily dosage is indicated to be 4-2,000 mg., e.g., 4-200 mg. for the more active compounds. The daily dosage of the compound of Example 2 is indicated to be 4-200 mg., preferably 10-40 mg , for most larger primates such as humans. For administration by injection, a dosage somewhat lower than would be used for oral administration of the same active substance to the same host having the same condition is usually employed. However, the above dosages are also typically used for i.v. administration.

The daily dosage may be administered in a single dose but more typically is administered in two to four equal portions, typical doses being 1-2,000 mg. Often, a small dosage is administered initially, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.

A typical dosage unit for oral administration may contain 1-500 mg. of a compound of Formula I.

The compounds of Formula I may be formulated into conventional pharmaceutical compositions and administered by any conventional mode of administration, in particular enterally, e.g., in the form of capsules or tablets, or parenterally, e.g., in the form of sterile injectable solutions or suspensions. The pharmaceutical compositions comprise a compound of Formula I and at least one pharmaceutically acceptable solid or liquid carrier (or diluent). They may be formulayed in conventional manner. The compounds of each subgroup thereof may likewise be formulated into such pharmaceutical compositions and administered by such routes.

The compounds of Formula I (including those of each subgroup thereof) may be formulated into such pharmaceutical compositions containing an amount of the active substance that is effective for inhibiting cholesterol biosynthesis in unit dosage form and such compositions comprising at least one solid pharmaceutically acceptable carrier.

A representative formulation suitable for encapsulation in a hard gelatin capsule by conventional techniques is: Compound of Formula I, e.g., the compound of

    ______________________________________                                         Compound of Formula I, e.g., the compound of                                   ______________________________________                                         Example 2                 5 mg.                                                Corn starch              244 mg.                                               Magnesium stearate        1 mg.                                                ______________________________________                                    

The following examples show representative compounds encompassed by this invention and their synthesis. However, it should be understood that they are for purposes of illustration only.

EXAMPLE 1 Ethyl (±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-3"-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate ##STR26##

Step 1 (Reaction CB)

(2-Oxo-2-phenylethyl)triphenylphosphonium bromide (Compound CII)

50.0 g. (251mmoles) of α-bromoacetophenone (Compound CI) and 65.9 g. (251 mmoles) of triphenylphosphine are stirred in 500 ml. of toluene at 20°-25° C. under nitrogen for 16 hours, and the resulting solid is collected by filtration, rinsed with toluene and rinsed with diethyl ether to obtain the product as a white powder (107.98 g. (93%)).

Step 2 (Reaction CC)

(E)-4-Methyl-1-phenylpent-2-en-1-one (Compound CIV)

A solution of 6.64 g. (289 mmoles) of sodium in 250 ml. of absolute ethanol is quickly added dropwise to a suspension of 133.3 g. (289 mmoles) of Compound CII in 1 l of absolute ethanol stirred at 20°-25° C., the suspension is gently warmed until a clear solution results, 31.5 ml. (25.0 g.; 347 mmoles) of isobutyraldehyde is added dropwise to the solution, and the reaction mixture is refluxed for 16 hours and cooled to 20°-25° C., the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is evaporated at reduced pressure, the resulting oily solid is triturated with diethyl ether, and the insoluble material is removed by filtration. The diethyl ether solution is washed with water, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residue is triturated with diethyl ether, any insoluble material is removed by filtration, and the diethyl ether is evaporated at reduced pressure to obtain a clear yellow liquid which is fractionally vacuum distilled through a vacuum jacketed Vigreux column to obtain the product as a clear liquid (22.8 g.), b.p. 90°-92° C./˜1 mm. Hg.

Step 3 (Reaction CE)

Ethyl (±)-2-[1'-(1"-methylethyl)-2'-oxo-2'-phenylethyl]-1,3-dithiolane-2-carboxylate (Compound CVI)

83 ml. of 1.65M. n-butyllithium/hexane (138 mmoles) is added via syringe to a solution of 20.2 ml. (14.58 g.; 144 mmoles) of diisopropylamine in 200 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at -78° C., the reaction mixture is warmed to 0° C. and cooled to -78° C., 18.7 ml. (23.35 g.; 131 mmoles) of ethyl 1,3-dithiolane-2-carboxylate (Compound CV) is added dropwise to the reaction mixture stirred at -78° C., the reaction mixture is stirred at -78° C. for 30 minutes, a solution of 22.749 g. (131 mmoles) of Compound CIV in 50 ml. of dry tetrahydrofuran (distilled from ketyl) is added dropwise with stirring at -78° C., and the reaction mixture is stirred at -78° C. for 3 hours, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is quenched at -78° C. with saturated ammonium chloride solution and warmed to 20°-25° C., the tetrahydrofuran is evaporated at reduced pressure, and the residue is partitioned between ethyl acetate and water. The aqueous phase is acidified to about pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residue is triturated with diethyl ether to obtain the crude product as a white solid (27.13 g.).

Step 4 (Reaction CF)

Ethyl (±)-2,5-dioxo-3-(1'-methylethyl)-5-phenylpentanoate (Compound CVII)

A solution of 27.1 g. (76.9 mmoles) of crude Compound CVI from Step 3 in 200 ml. of acetonitrile is added dropwise to a solution of 82.1 g. (461.3 mmoles) of N-bromosuccinimide in 500 ml. of a 4:1 mixture of acetonitrile and water stirred at 0° C., the reaction mixture is stirred at 0° C. for 4.5 hours, sufficient saturated sodium carbonate solution is added to obtain a clear solution, the acetonitrile is evaporated at reduced pressure, the residue is partitioned between ethyl acetate and water, the aqueous phase is acidified to about pH 2 with 10% aqueous hydrochloric acid and extracted with ethyl acetate, and the ethyl acetate layers are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as a clear yellow liquid (23.49 g.).

Step 5 (Reaction CG)

Ethyl 1-(4'-fluorophenyl)-3-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxylate (Compound CIX)

24.59 g. (89 mmoles) of crude Compound CVII from Step 4 and 16.9 ml. (19.8 g.; 178 mmoles) of 4-fluoroaniline are stirred at 0° C. in 350 ml. of toluene, a solution of 5.9 ml. (10.13 g.; 53.4 mmoles) of titanium tetrachloride in 50 ml. of hexane is added dropwise with stirring at 0° C., and the reaction mixture is allowed to slowly warm to 20°-25° C. and refluxed for 16 hours, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is filtered through a pad of Celite, the Celite is rinsed with ethyl acetate, and the rinse and filtrate are combined and evaporated at reduced pressure to obtain a brown solid (25.1 g.). The brown solid is recrystallized from absolute ethanol to obtain slightly colored needles (16.74 g.), a second crop is obtained from the absolute ethanol (2.87 g.), and the two crops are combined and recrystallized from absolute ethanol to obtain the product as a white powder (15.49 g.).

A small sample is dissolved in the minimum amount of methylene chloride and flash chromatographed on 250 g. of 230-400 mesh A.S.T.M. silica gel utilizing 25% diethyl ether/hexane as the eluant, the eluant is evaporated, and the residue is recrystallized from absolute ethanol to obtain an analytical sample, m.p. 107°-110° C.

Step 6 (Reaction AA)

1-(4'-Fluorophenyl)-3-(1'-methylethyl)-5-phenyl-1H-pyrrole-2methanol (Compound CX)

A solution of 15.0 g. (42.7 mmoles) of Compound CIX in 100 ml. of dry tetrahydrofuran (distilled from ketyl) is added dropwise to a suspension of 4.86 g. (128.1 mmoles) of lithium aluminum hydride in 150 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at 0° C., and the reaction mixture is allowed to warm to 20°-25° C., stirred at 20°-25° C. for 3 hours and cooled to 0° C., the reaction mixture being stirred under dry nitrogen throughout. The reaction mixture is quenched at 0° C. with water, the white gum is removed by filtration, the small aqueous phase is separated and the organic phase is washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a white solid (12.59 g.) which is recrystallized from diethyl ether/hexane to obtain the product as a white powder (6.58 g.). The mother liquor is evaporated at reduced pressure, and the residue is recrystallized from methylene chloride/hexane to obtain a second crop (1.903 g.). Total yield: 8.48 g. (64%).

Revised procedure:

A solution of 29.6 g. (84.2 mmoles) of Compound CIX in 250 ml. of dry diethyl ether is added dropwise to a suspension of 9.6 g. (252.6 mmoles) of lithium aluminum hydride in 250 ml. of dry diethyl ether stirred at 0° C. under dry nitrogen, and the reaction mixture is stirred at 0° C. under dry nitrogen for 2 hours. The reaction mixture is quenched at 0° C. with water and filtered. The filtrate is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as a white solid (23.92 g. (92%)).

Step 7 (Reaction AB) 1-(4'-Fluorophenyl)-3-(1'-methylethyl)-5-phenyl-1H-pyrrole-2carboxaldehyde (Compound CXII)

A solution of 7.8 g. (25.2 mmoles) of Compound CX in 200 ml. of dry acetone (dried over 4Å molecular sieves) is added dropwise to a mixture of 483 mg. (0.5 mmole) of tris(triphenylphosphine)ruthenium(II) chloride (Compound CXI) and 8.62 g. (50.4 mmoles) of N-methylmorpholine-N-oxide. monohydrate in 100 ml. of dry acetone (dried over 4Å. molecular sieves) stirred at 20°-25° C., and the reaction mixture is stirred at 20°-25° C. for 4 hours, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is filtered through 230-400 mesh A.S.T.M. silica gel, the silica gel is rinsed with diethyl ether, and the rinse and filtrate are combined and evaporated at reduced pressure to obtain a tan solid. The tan solid is dissolved in the minimum amount of methylene chloride and flash chromatographed on 450 g. of 230-400 mesh A.S.T.M. silica gel utilizing 25% diethyl ether/hexane as the eluant, and the eluant is evaporated at reduced pressure to obtain the product as a flocculant white solid (5.3 g. (68%)), m.p. 135°-139° C.

Revised procedure:

A solution of 24 g. (77.6 mmoles) of crude Compound CX (Step 6, revised procedure) in 250 ml. of dry acetone is added dropwise to a mixture of 1.5 g. (1.6 mmoles) of Compound CXI and 18 g. (154 mmoles) of N-methylmorpholine-N-oxide monohydrate in 250 ml. of dry acetone stirred at 20°-25° C., and the reaction mixture is stirred at 20°-25° C. for 4 hours, the reaction mixture being maintained under dry nitrogen throughout. 250 g. of 230-400 mesh A.S.T.M. silica gel is added, and the slurry is filtered through a 2 l. sintered glass funnel about one half full of the same silica gel. The silica gel is washed with 2 1. of 25% diethyl ether/hexane, and the filtrate and washing are combined and evaporated at reduced pressure. The obtained flocculant yellow solid is recrystallized from diethyl ether to obtain the product (13.12 g.). Additional product may be obtained from the mother liquor.

Step 8 (Reaction AF)

Ethyl(E)-3-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-enoate (Compound CXIV)

1.03 g. of 60% sodium hydride/mineral oil (25.7 mmoles) is washed twice with hexane and suspended in 100 ml. of dry tetrahydrofuran (distilled from ketyl), the suspension is stirred at 20°--15° C. approximately 1 ml. of triethyl phosphonoacetate (Compound CXIII) is added to initiate the reaction, the reaction mixture is cooled to -20°--15° C., approximately 3.9 ml. of triethyl phosphonoacetate is added dropwise with stirring at -20°--15° C. (the total amount of triethyl phosphonoacetate being 4.9 ml. (5.48 g.; 24.45 mmoles)), the reaction mixture is stirred at -20°--15° C. for 1 hour, a solution of 5.0 g. (16.3 mmoles) of Compound CXII in 50 ml. of dry tetrahydrofuran (distilled from ketyl) is added dropwise with stirring at -20°--15° C., and the reaction mixture is allowed to warm to 20°-25° C., refluxed for 3 hours and stirred at 20°-25° C. for 16 hours, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is diluted with diethyl ether and extracted with water, and the aqueous phase is reextracted with diethyl ether. The organic phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a white solid which is recrystallized from diethyl ether to obtain the product as a white powder (4.877 g.). A second crop is obtained from diethyl ether/hexane (0.66 g.). Total yield: 5.54 g. (90%).

An analytical sample is obtained by recrystallization of a small sample from diethyl ether/hexane, m.p. 145°-147.5° C.

Step 9 (Reaction AG)

(E)-3-[1'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-ol (Compound CXV)

44 ml. of 1.5M. diisobutylaluminum hydride/toluene (66 mmoles) is added dropwise to a solution of 5.0 g. (13.25 mmoles) of Compound CXIV in 100 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at -78° C., and the reaction mixture is stirred at -78° C. for 1 hour, the reaction mixture being stirred under dry nitrogen throughout. The reaction mixture is quenched at -78° C. with water and warmed to 20°-25° C., sufficient 10% hydrochloric acid is added to dissolve the gel, and the mixture is extracted twice with diethyl ether. The diethyl ether extracts are combined, washed with saturated sodium bicarbonate solution, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residue is recrystallized from diethyl ether to obtain the product as a white powder (3.1 g.), m.p. 142°-148° C. The mother liquor is evaporated at reduced pressure, the residue is dissolved in the minimum amount of methylene chloride and flash chromatographed on 150 g. of 230-400 mesh A.S.T.M. silica gel utilizing 50% diethyl ether/hexane as the eluant, and the eluant is evaporated at reduced pressure to obtain additional product as a tan powder (0.53 g.). Total yield: 3.63 g. (82%).

Step 10 (Reaction AH)

(E)-3-[1'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1-H-pyrrol-2'-yl]prop-2-en-1-al (Compound CXVI)

A solution of 3.3 g. (9.84 mmoles) of Compound CXV in 150 ml. of dry acetone (dried over 4Å. molecular sieves) is added dropwise to a mixture of 283 mg. (0.3 mmole) of tris(triphenylphosphine)ruthenium(II) chloride (Compound CXI) and 2.31 g. (19.68 mmoles) of N-methylmorpholine-N-oxide.monohydrate in 100 ml. of dry acetone (dried over 4Å. molecular sieves) stirred at 20°-25° C., the reaction mixture is stirred at 20°-25° C. for 3 hours, an additional 1.15 g. (9.84 mmoles) of N-methylmorpholine-N-oxide.monohydrate is added, the reaction mixture is stirred at 20°-25° C. for 2 hours, an additional 189 mg. (0.2 mmole) of tris(triphenylphosphine)ruthenium(II) chloride is added, and the reaction mixture is stirred at 20°-25° C. for 16 hours, the reaction mixture being stirred under dry nitrogen throughout. The reaction mixture is filtered through a pad of Celite and evaporated at reduced pressure to obtain a dark green oily solid which is dissolved in the minimum amount of methylene chloride and flash chromatographed on 250 g. of 230-400 mesh A.S.T.M. silica gel utilizing 25% diethyl ether/hexane as the eluant. The eluant is evaporated at reduced pressure to obtain the product as a yellow solid (2.49 g. (76%)), m.p. 180°-184° C. Step 8

Step 8A (Reaction AI)

(E)-3-[1'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H- pyrrol-2'-yl]prop-2-en-1-al (Compound CXVI)

29 ml. of 1.7M. t-butyllithium/pentane (49.3 mmoles) is added dropwise to a solution of 2.6 ml. (3.72 g.; 24.6 mmoles) of cis-1-bromo-2-ethoxyethylene in 50 ml. of dry tetrahydrofuran stirred at -78° C., the reaction mixture is stirred at -78° C. for 4 hours, a solution of 5.0 g. (16.3 mmoles) of Compound CXII in 25 ml. of dry tetrahydrofuran is added dropwise with stirring at -78° C., and the reaction mixture is stirred at -78° C. for 45 minutes, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is quenched with saturated ammonium chloride solution and warmed to 20°-25° C., the tetrahydrofuran is evaporated at reduced pressure, and the residue is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, and the two diethyl ether phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to an orange gum at reduced pressure. The orange gum is dissolved in 100 ml. of a 9:1 mixture of tetrahydrofuran and water, 0.31 g. (1.63 mmoles) of p-toluenesulfonic acid.monohydrate is added, the reaction mixture is stirred at 20°-25° C. for 4 hours, the tetrahydrofuran is evaporated at reduced pressure, and the residue is partitioned between chloroform and water. The aqueous phase is extracted with chloroform, and the chloroform phases are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a green solid. The green solid is dissolved in the minimum amount of chloroform, adsorbed onto 25 g. of 230-400 mesh A.S.T.M. silica gel and flash chromatographed on 400 g. of the same silica gel utilizing 1:1 diethyl ether/hexane as the eluant. The eluant is evaporated at reduced pressure to obtain the crude product as an orange solid (4.28 g. (79%)).

Step 11 (Reaction A)

Ethyl (±)-(E)-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]-5-hydroxy-3-oxohept-6-enoate (Compound CXVIII)

528 mg. (13.2 mmoles) of 60% sodium hydride/mineral oil is washed twice with hexane, the sodium hydride is suspended in 50 ml. of dry tetrahydrofuran (distilled from ketyl), the suspension is cooled to -b 20°--15° C., 1.53 ml. (1.56 g.; 12.0 mmoles) of ethyl acetoacetate is added dropwise, the reaction mixture is stirred at -20°--15° C. for 30 minutes, 7.6 ml. of 1.65M. -n-butyllithium/hexane (12.54 mmoles) is added dropwise with stirring at -20°--15° C., the reaction mixture is stirred at -20°--15° C. for 15 minutes, a solution of 2.0 g. (6.0 mmoles) of Compound CXVI in 50 ml. of dry tetrahydrofuran (distilled from ketyl) is added dropwise with stirring at -15° C., and the reaction mixture is stirred at -15° C. for 2.5 hours, the reaction mixture being stirred under dry argon throughout. The reaction mixture is quenched at -15° C. with saturated ammonium chloride solution and warmed to 20°-25° C., the tetrahydrofuran is evaporated at reduced pressure, the residue is partitioned between diethyl ether and water, the aqueous phase is extracted with diethyl ether, and the diethyl ether phases are combined, washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated at reduced pressure to a brown oil. The brown oil is dissolved in the minimum amount of methylene chloride and flash chromatographed on 250 g. of 230-400 mesh A.S.T.M. silica gel utilizing 1:1 diethyl ether/hexane as the eluant, and the eluant is evaporated at reduced pressure to obtain the product as a yellow solid (2.51 g. (90%)).

A small sample is recrystallized from diethyl ether/hexane to obtain an analytical sample, m.p. 98°-101° C.

Revised procedure:

1.16 g. of 60% sodium hydride/mineral oil (29 mmoles) is washed with hexane, the sodium hydride is suspended in 100 ml. of dry tetrahydrofuran, the suspension is cooled to -20°--15° C., 3.3 ml. (3.37 g.; 25.9 mmoles) of ethyl acetoacetate is added dropwise, the reaction mixture is stirred at -20°--15° C. for 30 minutes, 17 ml. of 1.6M. n-butyllithium/hexane (27.2 mmoles) is added dropwise with stirring at -20°--15° C., the reaction mixture is stirred at -20°--15° C., for 15 minutes, a solution of 4.28 g. (12.8 mmoles) of crude Compound CXVI (from Step 8A) in 100 ml. of dry tetrahydrofuran is added dropwise with stirring at -20°--15° C., and the reaction mixture is stirred at -20°--15° C. for 30 minutes, the reaction mixture being stirred under dry nitrogen throughout. The reaction mixture is quenched with saturated ammonium chloride solution and warmed to 20°-25° C., the tetrahydrofuran is evaporated at reduced pressure, and the residue is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, and the diethyl ether phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a dark orange oil. The dark orange oil is dissolved in the minimum amount of methylene chloride and flash chromatographed on 500 g. of 230-400 mesh A.S.T.M. silica gel utilizing 1:1 diethyl ether/hexane as the eluant. The fractions containing relatively pure product (as determined by thin layer chromatography) are combined and evaporated at reduced pressure to obtain the product as an oily solid (2.33 g.). The other fractions containing the product are combined, evaporated at reduced pressure, dissolved in the minimum amount of methylene chloride and flash chromatographed on 350 g. of 230-400 mesh A.S.T.M. silica gel utilizing, successively, 40%, 50% and 80% diethyl ether/hexane as the eluants. The fractions containing the product are combined and evaporated at reduced pressure to obtain additional product as an orange oil that solidifies upon standing (2.54 g.). Total yield: 4.87 g. (80.5%).

The product is a racemate which may be resolved to obtain the 5R and 5S enantiomers.

Step 12 (Reaction B)

Ethyl (±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate (Compound CXIX)

(a) 4.32 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (4.32 mmoles) is added quickly dropwise to a solution of 1.0 g. (2.16 mmoles) of Compound CXVIII in 25 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at 20°-25° C., air is bubbled through the solution for 1 minute, the solution is stirred at 20°-25° C. for 1 hour and cooled to -78° C., 408 mg. (10.8 mmoles) of sodium borohydride is added with stirring at -78° C., and the reaction mixture is stirred at -50° C. for 16 hours and allowed to slowly warm to -20° C. to complete the reaction, the reaction mixture being stirred under dry nitrogen throughout. The reaction mixture is quenched at -20° C. with 10% hydrochloric acid (to pH 2), allowed to warm to 20°-25° C. and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, and the organic phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to a clear yellow oil. A small amount of isopropanol is added, and the isopropanol is evaporated at reduced pressure to obtain a yellow solid.

(b) The cyclic boron ester product of Part (a) is dissolved in methanol with heating and the methanol is evaporated at reduced pressure, and this procedure is repeated twice more to obtain a white solid which is recrystallized from methylene chloride/hexane to obtain the product as a flocculant white solid (295.2 mg. (29%)), m.p. 140°-142° C.

Revised procedure:

(a) 10.0 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (10.0 mmoles) is added quickly dropwise to a solution of 2.33 g. (5.0 mmoles) of Compound CXVIII (Step 11, revised procedure, first fraction) in 100 ml. of 4:1 dry tetrahydrofuran/methanol stirred at 20°-25° C., air is bubbled in for 1 minute, the reaction mixture is stirred at 20°-25° C. for 1 hour and cooled to -78° C., 567 mg. (15.0 mmoles) of sodium borohydride is added, and the reaction mixture is stirred at -78° C. for 2 hours, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is quenched at -78° C. with 4 ml. of acetic acid and warmed to 20°-25° C., the solvent is evaporated at reduced pressure, and the residue is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, and the diethyl ether phases are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a yellow solid (3.31 g.).

(b) The cyclic boron ester product of Part (a) is dissolved in methanol with heating and the methanol is evaporated at reduced pressure, and this procedure is repeated twice more to obtain an oily yellow solid which is recrystallized from methylene chloride/hexane to obtain the product as a white powder, m.p. 144.5°-146.5° C.

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter exceeds 9:1 (initial batch (m.p. 140°-142° C.)) or 19:1 (revised procedure batch (m.p. 144.5°-146.5° C.)), which mixtures may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate, may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a non-stereoselective reduction would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 2 Sodium (±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate (Reaction Q) ##STR27##

0.1 ml. of 0.5N. sodium hydroxide solution (0.05 mmole) is quickly added dropwise to a suspension of 25 mg. (0.054 mmole) of Compound CXIX in 5 ml. of absolute ethanol, and the reaction mixture is stirred at 20°-25° C. for 2 hours, diethyl ether is added, and the pale yellow precipitated product is collected, stirred in diethyl ether and collected by filtration (18 mg. (77%)), m.p. 175°-185° C. (dec.) (yellows at 145° C.)

N.M.R. (CD₃ OD+CDCl₃): 1.21 (m, 6H), 1.60 (m, 2H), 2.29 (m, 2H), 3.12 (m, 1H), 3.95 (m, 1H), 4.20 (m, 1H), 5.40 (dd (J₁ =15 Hz., J₂ =7.5 Hz.), 1H), 6.22 (d (J=15 Hz.), 1H), 6.30 (s, 1H), 7.08 (m, 9H)

Revised procedure:

19 ml. of 0.5N. sodium hydroxide solution (9.5 mmoles) is added dropwise to a suspension of 4.67 g. (10.0 mmoles) of Compound CXIX (Example 1, Step 12, revised procedure) in about 200 ml. of absolute ethanol stirred at 20°-25° C., and the reaction mixture is stirred at 20°-25° C. for 3 hours. The reaction mixture is concentrated at reduced pressure by about one third, and diethyl ether is added to obtain a pale yellow powder (3.7 g.). The powder is stirred in diethyl ether at 20°-25° C. for 30 minutes, and the fine pale yellow product is collected by filtration. M.p. 203°-206° C. (dec.) Additional product is obtained from the mother liquors. The combined yield of this batch and a similar smaller one is about 81%.

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter exceeds 9:1 (initial batch (m.p. 175°-185° C. (dec.))) or 19:1 (revised procedure batch (m.p. 203°-206° C. (dec.))), which mixtures may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate, may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a starting material synthesized by using a non-stereoselective reduction in Step 12 of Example 1 would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

Example 3 Ethyl (E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate ##STR28##

Step 1 (Reaction CD)

(E)-3-(4'-Fluorophenyl)-1-phenylprop-2-en-1-one (Compound CXXIII)

52.0 g. (433 mmoles) of acetophenone is added to a solution of 21.8 g. (545 mmoles) of sodium hydroxide in a mixture of 196 ml. of water and 122.5 ml. of 95% ethanol stirred at 20°-25° C., the resulting suspension is cooled to 0°-5° C., and 53.74 g. (433 mmoles) of 4-fluorobenzaldehyde is added portionwise, the temperature of the reaction mixture rising to 20° C. during the addition. The solidified reaction mixture is kept at 20°-25° C. for 3 hours and refrigerated for 16 hours. The solid is collected by filtration, rinsed with about 2 l. of water until the rinses are neutral, rinsed with 200 ml. of cold 95% ethanol and recrystallized from 95% ethanol to obtain the product as yellow flakes (66.25 g. (68%)), m.p. 83°-86° C.

Step 2 (Reaction CE)

Ethyl (±)-2-[1'-(4"-fluorophenyl)-3'-oxo-3'-phenylpropyl]-1,3-dithiolane-2-carboxylate (Compound CXXIV)

The product is obtained from 25.0 g. (110.5 mmoles) of Compound CXXIII and 16 ml. (19.7 g.; 110.5 mmoles) of Compound CV utilizing 17 ml. (12.3 g.; 121.5 mmoles) of diisopropylamine and 73.0 ml. of 1.6M. n-butyllithium/hexane (116.8 mmoles) substantially in accordance with the process of Step 3 of Example 1, the principal difference being that subsequent to the evaporation of the tetrahydrofuran the residue is partitioned between diethyl ether and water. The crude product is obtained as a viscous clear brown liquid (45.86 g. (100%)).

Step 3 (Reaction CF)

Ethyl (±)-2,5-dioxo-3-(4'-fluorophenyl)-5-phenylpentanoate (Compound CXXV)

The product is obtained from 45.86 g. (≦110.5 mmoles) of crude Compound CXXIV from Step 2 utilizing 118 g. (663 mmoles) of N-bromosuccinimide substantially in accordance with the process of Step 4 of Example 1, the principal difference being that the reaction mixture is stirred at 0° C. for 3 hours. The obtained cloudy brown viscous oil is chromatographed on a Waters Prep-500 HPLC utilizing a silica gel column, methylene chloride as the eluant and a flow rate of 300 ml./min. The fractions containing a substantial amount of product are combined and evaporated at reduced pressure to obtain the crude product (16.33 g.).

Step 4 (Reaction CG)

Ethyl 3-(4'-fluorophenyl)-1-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxylate (Compound CXXVII)

The product is obtained from 16.33 g. (≦49.7 mmoles) of crude Compound CXXV from Step 3 and 15 ml. (10.28 g.; 173.95 mmoles) of isopropylamine utilizing 30 ml. of 1.0M. titanium tetrachloride/hexane (30 mmoles) substantially in accordance with the process of Step 5 of Example 1, the principal difference being that the reaction mixture is stirred at 20°-25° C. for 30 minutes prior to being refluxed. The obtained viscous orange oil solidifies upon standing, and the obtained solid is recrystallized from absolute ethanol to obtain the product as white needles (6.25 g. (36%)). A previous batch melted at 97°-100° C.

Step 5 (Reaction AA)

3-(4'-Fluorophenyl)-1-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-methanol (Compound CXXVIII)

The product is obtained from 6.25 g. (17.8 mmoles) of Compound CXXVII utilizing 2.0 g. (53.4 mmoles) of lithium aluminum hydride substantially in accordance with the process of Step 6 of Example 1, the principal difference being that the reaction mixture is stirred at 0° C. for 1 hour and at 20°-25° C. for 2 hours. The obtained white powder is recrystallized from diethyl ether/hexane to obtain the product as a white powder (4.83 g. (88%)).

Step 6 (Reaction AB)

3-(4'-Fluorophenyl)-1-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxaldehyde (Compound CXXIX)

The product is obtained from 9.5 g. (30.7 mmoles) of Compound CXXVIII utilizing 589 mg. (0.61 mmole) of tris(triphenylphosphine)ruthenium(II) chloride and 10.51 g. (61.4 mmoles) of N-methylmorpholine-N-oxide.monohydrate substantially in accordance with the process of Step 7 of Example 1, the principal difference being that the reaction mixture is stirred at 20°-25° C. for just 1 hour. The obtained brown solid is dissolved in diethyl ether, the insoluble material is removed by filtration, the diethyl ether is evaporated at reduced pressure to obtain a white solid, and the white solid is recrystallized from diethyl ether to obtain the product as a white powder (7.43 g.), m.p. 118°-122° C. A second crop is also obtained (0.84 g.).

Step 7 (Reaction AF)

Ethyl (E)-3-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-enoate (Compound CXXX)

The product is obtained from 7.3 g. (24 mmoles) of Compound CXXIX and 7.2 ml. (8.07 g.; 36 mmoles) of triethyl phosphonoacetate utilizing 1.51 g. (37.8 mmoles) of 60% sodium hydride/mineral oil substantially in accordance with the process of Step 8 of Example 1, the principal differences being that the reaction mixture is refluxed for 4 hours and the stirring at 20°-25° C. for 16 hours is omitted. The obtained yellow oil solidifies upon standing, and the resulting solid is recrystallized from diethyl ether/hexane to obtain the product as a yellow powder (6.46 g. (71%)), m.p. 84°-87° C.

Step 8 (Reaction AG)

(E)-3-[3'-(4"-Fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-ol (Compound CXXXI)

The product is obtained from 6.3 g. (17 mmoles) of Compound CXXX utilizing 45 ml. of 1.5M. diisobutylaluminum hydride/toluene (67.5 mmoles) substantially in accordance with the process of Step 9 of Example 1, the principal difference being that the reaction is carried out at 0° C. for 2 hours. However, the use of a lower reaction temperature, e.g., -78° C., should give a much better yield of the product.

Step 9 (Reaction AH)

(E)-3-[3'-(4"-Fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-al (Compound CXXXII)

The product is obtained from 200 mg. (0.6 mmole) of Compound CXXXI utilizing 14 mg. (0.015 mmole) of tris(triphenylphosphine)ruthenium(II) chloride and 14 mg. (1.2 mmoles) of N-methylmorpholine-N-oxide.monohydrate substantially in accordance with the process of Step 10 of Example 1, the principal differences being that no additional N-methylmorpholine-N-oxide.monohydrate is added, the second batch (14 mg.; 0.015 mmole) of the ruthenium salt is added after 2 hours at 20°-25° C., and 1:1 diethyl ether/hexane is utilized as the eluant in the flash chromatography. The product is obtained as a bright yellow foam.

Step 10 (Reaction A)

Ethyl (±)-(E)-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]-5-hydroxy-3-oxohept-6-enoate (Compound CXXXIII)

The product is obtained from 581 mg. (1.74 mmoles) of Compound CXXXII and 0.44 ml. (454 mg.; 3.48 mmoles) of ethyl acetoacetate utilizing 153 mg. of 60% sodium hydride/mineral oil (3.83 mmoles) and 2.2 ml. of 1.65M. n-butyllithium/hexane (3.63 mmoles) substantially in accordance with the process of Step 11 of Example 1, the principal differences being that the reaction mixture is stirred at -20°--15° C. for 15 minutes prior to the addition of the n-butyllithium/hexane and for just 10 minutes subsequent to the addition of Compound CXXXII, and 60% diethyl ether/hexane is used as the eluant in the flash chromatography. The product is obtained as a viscous yellow oil (545.3 mg.).

The product is a racemate that may be resolved by conventional means to obtain the 5R and 5S enantiomers.

Step 11 (Reaction B)

Ethyl (E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate (Compound CXXXIV)

(a) 1.18 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (1.18 mmoles) is quickly added dropwise to a solution of 273.2 mg. (0.59 mmole) of Compound CXXXIII in 5 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at 20°-25° C., air is bubbled into the reaction mixture for 1 minute, the reaction mixture is stirred at 20°-25° C. for 1 hour and cooled to -78° C., 56 mg. (1.475 mmoles) of sodium borohydride is added with stirring at -78° C., the reaction mixture is stirred at -50° C. for 16 hours, an additional 56 mg. (1.475 mmoles) of sodium borohydride is added with stirring at -50° C., and the reaction mixture is allowed to slowly warm to -10° C. and is stirred at -10° C. for 1 hour, the reaction mixture being maintained under dry nitrogen throughout. The reaction mixture is quenched at -10° C. with 10% hydrochloric acid (to pH 2), warmed to 20°-25° C. and partitioned between diethyl ether and water, and the aqueous phase is extracted with diethyl ether. The diethyl ether phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the cyclic boron ester as a clear yellow liquid.

(b) The cyclic boron ester product of Part (a) is dissolved in methanol with gentle heating and the methanol is evaporated at reduced pressure, this process is repeated twice more, and the obtained yellow oil is dissolved in the minimum amount of methylene chloride and flash chromatographed on 150 g. of 230-400 mesh A.S.T.M. silica gel utilizing 80% diethyl ether/hexane and then diethyl ether as the eluants. Evaporation of the eluant yields the product as a clear green oil (166.1 mg.).

N.M.R. (CDCl₃): 1.28 (t, 3H), 1.50 (d, 6H), 1.60 (m, 2H), 2.48 (m, 2H), 3.28 (m, 1H), 3.71 (m, 1H), 4.20 (m, 3H), 4.46 (m, 1H), 4.59 (m, 1H), 5.56 (dd (J₁ =15 Hz., J₂ =5 Hz.), 1H), 6.14 (s, 1H), 6.75 (d (J=15 Hz.), 1H), 7.00 (t, 2H), 7.39 (m, 7H).

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is about 3:1, which mixture may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate, may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a nonstereoselective reduction would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 4 Ethyl (±)-erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate ##STR29##

A mixture of 120.4 mg. (0.26 mmole) of Compound CXXXIV, 24 mg. (0.39 mmole) of boric acid and 5 ml. of isopropanol is stirred at 80° C. for 3 hours, cooled to 20°-25° C. and evaporated at reduced pressure to obtain a yellow oil. The yellow oil is dissolved in isopropanol with warming, the isopropanol is evaporated at reduced pressure to obtain a yellow foam, the yellow foam is dissolved in the minimum amount of hot isopropanol, the solution is stored at 0° C. for 16 hours, and the mother liquor is decanted. The residual yellow wax is dissolved in methanol with gentle heating and the methanol is evaporated at reduced pressure and this process is repeated twice to obtain a clear yellow oil. The oil is crystallized from methylene chloride/hexane to obtain the product as a flocculant white solid (29.5 mg.), m.p. 105°-107° C.

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter exceeds 9:1, which mixture may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and S,5R enantiomers, of which the former is preferred.

EXAMPLE 5 Sodium (±)-erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate (Reaction Q) ##STR30##

0.08 ml. of 0.5N. sodium hydroxide solution (0.04 mmole) is added dropwise to a solution of 20 mg. (0.043 mmole) of Compound CXXXV in 2 ml. of absolute ethanol stirred at 20°-25° C., the reaction mixture is stirred at 20°-25° C. for 2 hours, the ethanol is evaporated at reduced pressure, the residue is dissolved in water, and the obtained solution is extracted with diethyl ether and lyophilized for 16 hours to obtain the product as a white powder (16.8 mg.), m.p. 185°-192° C. (dec.) (changes color at 135° C.)

N.M.R. (CD₃ OD+CDCl₃): 1.48 (m, 6H), 1.64 (m, 2H), 2.30 (m, 2H), 4.00 (m, 1H), 4.34 (m, 1H), 4.55 (m, 1H), 5.50 (dd (J₁ =15 Hz., J₂ =7.5 Hz.), 1H), 6.02 (s, 1H), 6.71 (d (J=15 Hz.), 1H), 7.00 (t (J=10 Hz.), 2H), 7.38 (m, 7H).

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter exceeds 9:1, which mixture may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate, may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a starting material synthesized by using a non-stereoselective reduction in Step 11 of Example 3 would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

Throughout the specification, the term "reduced pressure" denotes aspirator pressure. Where no solvent is specified in connection with a solution, the solvent is water, and all solvent mixtures are by volume. When a reaction is carried out under nitrogen, dry nitrogen is used to maintain anhydrous conditions (except where the reaction medium contains water).

All nuclear magnetic resonance spectra were taken at ambient temperature on a 200 MHz. spectrometer. All chemical shifts are given in p.p.m. (δ) relative to tetramethylsilane, and where a single δ value is given for anything other than a sharp singlet, it is its center point. In the N.M.R. data:

d=doublet

dd=doublet of a doublet

m=multiplet

s=singlet

t=triplet

Each of the compounds of the examples wherein Z is a group of Formula a wherein R₁₈ is a cation may be converted into the corresponding compounds wherein R₁₈ is hydrogen or a different cation M, particularly the latter, especially M', by the processes set forth in Reaction Scheme IV.

Each of the compounds of Examples 1-5 (including each of the possible isomers of the examples) may be administered to an animal, e.g., a larger primate, to inhibit cholesterol biosynthesis and thereby lower the blood cholesterol level for, for example, the treatment of atherosclerosis and hyperlipoproteinemia. The dosages are those set forth supra. 

What is claimed is:
 1. A compound of the formula ##STR31## wherein Pr is ##STR32## wherein R₁ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR33## wherein R₅, R₆ and R₇ are as defined below,R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR34## wherein R₈, R₉ and R₁₀ are as defined below, R₃ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR35## wherein R₁₁, R₁₂ and R₁₃ are as defined below, R₄ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR36## wherein R₁₄, R₁₅ and R₁₆ are as defined below, Pr' is ##STR37## wherein R₄ a is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR38## wherein R₁₄, R₁₅ and R₁₆ are as defined below, R₁ -R₄ are as defined above, and R₂₀ is as defined below, Pr" is ##STR39## wherein R₁ -R₄ and R_(4a) are as defined above, and R₃₄ -R₃₆ are as defined below, R₁₇ is hydrogen or C₁₋₃ alkyl, R_(17a) pk is C₁₋₃ alkyl, R₁₉ ' is C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl, each R₂₀ is independently C₁₋₃ alkyl, each of R₃₄, R₃₅ and R₃₆ is independently C₁₋₆ alkyl not containing an asymmetric carbon atom, X₁ is --(CH₂)m-- or (E)--CH═CH--, wherein m is 0, 1, 2 or 3, X₄ is --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, and X₅ is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --,wherein each of R₅, R₈, R₁₁ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R₆, R₉, R₁₂ and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R₇, R₁₀, R₁₃ and R₁₆ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A, B, C and D independently is trifluoromethyl, not more than one substituent on each of Rings A, B, C and D independently is phenoxy, and not more than one substituent on each of Rings A, B, C and D independently is benzyloxy,with the provisos that in Pr (i) the free valence is in the 2- or 3-position, (ii) the free valence is ortho to both R₁ and R₂, and (iii) R₃ is ortho to R₂.
 2. A compound according to claim 1 having the formula ##STR40##
 3. A compound according to claim 2 wherein Pr is ##STR41##
 4. A compound according to claim 3 whereinR₁ is ##STR42## R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, R₄ is ##STR43## and X₁ is --CH₂ CH₂ -- or (E)--CH═CH--,wherein each of R₅ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ -alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R₆ and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R₇ and R₁₆ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A and D independently is trifluoromethyl, not more than one substituent on each of Rings A and D independently is phenoxy, and not more than one substituent on each of Rings A and D independently is benzyloxy.
 5. A compound according to claim 4 whereinR₂ is C₁₋₄ alkyl not containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₂ alkyl, each of R₅ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluromethyl, fluoro or chloro, each of R₆ and R₁₅ is independently hydrogen, C₁₋₂ alkyl, fluoro or chloro, each of R₇ and R₁₆ is independently hydrogen or methyl, R₁₉ is C₁₋₃ alkyl, and X₁ is (E)--CH═CH--.
 6. A compound according to claim 5 whereinR₃ is hydrogen or methyl, each of R₅ and R₁₄ is independently hydrogen, methyl of fluoro, each of R₆ and R₁₅ is independently hydrogen or methyl, R₇ is hydrogen, R₁₆ is hydrogen, and R₁₉ ' is C₁₋₂ alkyl.
 7. The compound according to claim 6 having the formula ##STR44##
 8. The compound according to claim 2 having the formula ##STR45##
 9. A compound according to claim 2 whereinPr is ##STR46##
 10. A compound according to claim 9 whereinR₁ is ##STR47## R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, R₄ is ##STR48## and X₁ is --CH₂ CH₂ -- or (E)--CH═CH--, wherein each of R₅ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ -alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R₆ and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R₇ and R₁₆ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A and D independently is trifluoromethyl, not more than one substituent on each of Rings A and D independently is phenoxy, and not more than one substituent on each of Rings A and D independently is benzyloxy.
 11. A compound according to claim 10 whereinR₂ is C₁₋₄ alkyl not containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₂ alkyl, each of R₅ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl, fluoro or chloro, each of R₆ and R₁₅ is independently hydrogen, C₁₋₂ alkyl, fluoro or chloro, each of R₇ and R₁₆ is independently hydrogen or methyl, R₁₉ ' is C₁₋₃ alkyl, and X₁ is (E)--CH═CH--.
 12. A compound according to claim 11 whereinR₃ is hydrogen or methyl, each of R₅ and R₁₄ is independently hydrogen, methyl or fluoro, each of R₆ and R₁₅ is independently hydrogen or methyl, R₇ is hydrogen, R₁₆ is hydrogen, and R₁₉ is C₁₋₂ alkyl.
 13. A compound according to claim 1 having the formula ##STR49##
 14. A compound according to claim 1 having the formula ##STR50##
 15. A compound according to claim 1 having the formula ##STR51##
 16. A compound according to claim 15 wherein Pr is ##STR52##
 17. A compound according to claim 16 whereinR₁ is ##STR53## R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbon atom, R₄ is ##STR54## R₁₇ is hydrogen or methyl, and X₄ is --CH═CH--,wherein each of R₅ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R₆ and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R₇ and R₁₆ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A and D independently is trifluoromethyl, not more than one substituent on each of Rings A and D independently is phenoxy, and not more than one substituent on each of Rings A and D independently is benzyloxy.
 18. A compound according to claim 17 whereinR₂ is C₁₋₄ alkyl not containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₂ alkyl, each of R₅ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl, fluoro or chloro, each of R₆ and R₁₅ is independently hydrogen, C₁₋₂ alkyl, fluoro or chloro, each of R₇ and R₁₆ is independently hydrogen or methyl, R₁₇ is hydrogen, R₁₉ ' is C₁₋₃ alkyl, and X₄ is (E)--CH═CH--.
 19. A compound according to claim 15 whereinPr is ##STR55##
 20. A compound according to claim 1 having the formula ##STR56## 